Article Type : Research Article
Authors : Dudhat KR
Keywords : Compression; Consolidation; Compaction; Improvement of Compaction
Tablets
are the most popular dosage form of all those that are available because, among
other advantages, they offer high-precision dose, efficient manufacturing, and
patient compliance. Two of the most crucial manufacturing phases in the
creation of tablets are compression (i.e., a reduction in consolidation) and
volume of the powder under consideration (as well as particle rearrangement)
(i.e., the development of an interparticulate connection to aid in compaction
stability). The efficacy of the compaction process is influenced by the
physico-technical properties of the pharmaceuticals and excipients as well as
the instrument parameters for force transmission rate and magnitude. Pre/main
compression force profiles and tablet manufacturing speed both have an impact
on the finished tablet's quality. Instrumented punches/dies, compaction
simulators, and instrumented tablet punching machines can all be used to study
the mechanical elements of tablet production. These could be used, among other
things, in pharmaceutical research and development to look into fundamental
compaction mechanisms, various process variables, scale-up parameters,
troubleshoot problems, create a compaction data library, and fingerprint new
active pharmaceutical ingredients (APIs) or excipients. The work of compaction,
elasticity/plasticity, and time-dependent deformation behaviour of the
under-discussed pharmaceutical powder are characterized using mathematical
models, force-time, force-distance, and die-wall force parameters of tablet manufacture.
Compression refers to a decrease in the bulk volume of materials as a result of the gaseous phase being displaced depicts the stages involved in powdered solids bulk reduction. The only forces that exist between the particles at the start of the compression process, when the powder is filled into the die cavity and before the upper punch enters the die cavity, are those that are related to the packing characteristics of the particles, the density of the particles, and the total mass of the material that is filled into the die cavity [1]. The packing qualities of the individual particles will determine the packing characteristics of the powder mass. When external mechanical forces are applied to a powder mass, the volume of the powder is usually reduced due to closer packing of the powder particles, and this is the primary mechanism of initial volume reduction in most circumstances [2]. However, when the stress grows, particle rearrangement becomes more difficult, and further compression results in particle deformation of some sort. The deformation is said to be elastic if it is reversible to a great extent after the load is removed, i.e. it behaves like rubber. When exposed to external forces, all solids deform elastically. Within the range of maximum force experienced in practice, elastic deformation becomes the major mechanism of compression with some medicinal compounds, such as acetylsalicylic acid [3, 4]. In some powdered solids, an elastic limit is reached, and loads over this level cause deformation that is not immediately reversible when the applied force is removed. In these circumstances, bulk volume reduction is caused by plastic deformation and/or viscous flow of particles, which are pressed into the remaining vacuum spaces, similar to how modelling clay behaves [5, 6]. When the shear strength is lower than the tensile or breaking strength, this process takes over. The greatest number of clean surfaces is said to be created by plastic deformation. Because plastic deformation is a time-dependent process, applying more force at a faster rate should result in fewer new clean surfaces being formed, resulting in weaker tablets. Furthermore, because the development of fresh clean surfaces is required for tablet formation, high concentrations or overmixing of elements that form weak bonds results in weak tablets [7]. Magnesium stearate, for instance, forms a weak binding and is quickly moistened. As a result, excessive magnesium stearate mixing may result in weak pills. Particles may be preferentially fragmented in materials with a shear strength greater than the tensile strength, and the smaller fragments then aid to fill in the adjacent air gaps [8]. Brittle fracture is most likely to occur with hard, brittle particles, and sucrose acts in this fashion. The ability of a material to deform in a specific way is determined by its lattice structure, particularly the presence of weakly connected lattice planes [9]. Brittle fracture results on clean surfaces that are brought into close proximity by the applied load. Small particles can deform plastically through a process known as microsquashing, regardless of how large particles behave, and the amount of fine powders in a sample can be considerable. Asperities sheared off larger, extremely irregular particles may behave similarly; thus, particle form is a significant consideration [10]. During compression, four stages of events are encountered:
Consolidation is defined as a rise in a material's
mechanical strength as a result of particle-particle interactions. The next
sections go over several powder consolidation mechanisms. When the surfaces of
two particles come close enough together (e.g., less than 50nm), their free
surface energy combine to form a strong attractive force. This is known as cold
welding. On a molecular scale, the nature of the bonds created is comparable to
that of the molecular structure of the inside of the particle surface, but the
surface area involved may be minimal. This theory is widely accepted as a
primary cause for a bed of powder's growing mechanical strength as compressive
forces increase [11]. On a macro scale, most particles encountered in practice
have an irregular form, resulting in a bed of powder with several points of
contact. Any load applied to the bed must pass through these particle
connections. However, at significant stresses, this transmission may result in
significant frictional heat build-up. If this heat is released, the local
temperature rise may be sufficient to promote melting of the particle contact
area, relieving stress in that particular region [12]. When the melt
solidifies, fusion bonding takes place, resulting in an increase in the mass's mechanical
strength. All of the deformation effects could be accompanied by the breaking
and development of new bonds between the particles, resulting in consolidation
as the new surfaces are forced together [13]. Another method for powder
consolidation is aspartic melting of the powder particles' local surfaces. The
temperature of the powder compact rises between 4 and 30 oC during compression,
depending on friction effects, individual material features, lubrication
efficiency, the magnitude and rate of application of compression forces, and
machine speed. Stress relaxation and plasticity increase as the tablet
temperature rises, whereas elasticity diminishes and powerful compacts form
[14]. As a result, material compression at high temperatures combined with
increased ductility should result in stronger tablets. Only with low melting
point materials, where even very hard asperities are forced into a more pliable
substance, is aspartic melting thought to be significant. The chemical nature
of the powder, the surface area of the contact point, contamination (including
film coating, such as magnesium stearate), and interparticulate distance all
influence the final tablet qualities [15]. The compression event into a series
of time intervals and suggested some useful concepts as a result [16].
These are the ones:
Jones' definitions are shown in as a diagrammatic
representation of the lower punch force trace from an eccentric press. Dwell
time cannot be calculated in this circumstance because force reaches a maximum
value and then rapidly falls, resulting in a peak with no plateau. However, in
some studies, the maximum force is sustained for lengthy periods of time, and
"dwell time" becomes relevant in these situations [17]. Furthermore,
rotary presses have a distinct, albeit extremely short, dwell period.
A particulate solid–gas system is compressed and consolidated as a result of an applied force. Compaction is a term used to describe the process of compacting soil. Compression results in a reduction in bulk volume due to the reduced gaseous phase. Closer packing of powder particles as a result of rearrangement is the fundamental process for initial volume reduction [18]. When the force is increased, particle deformation occurs, making rearrangement more difficult. Consolidation is characterized by an increase in mechanical strength due to particle–particle interactions, which happens later. When particles get closer to one another during the volume reduction process, bonds are created between them. The nature of the bonds formed is similar to the molecular structure of the particles' insides, but due to the roughness of the particles' surface, the actual surface area involved is limited [19]. Consolidation is the primary cause of rising mechanical costs. The ability of a material to undergo a volume decrease as a result of an applied pressure is defined and is illustrated by a plot of tablet porosity against compaction pressure [20]. Compatibility is defined as a material's ability to produce tablets of sufficient strength under the effect of densification, as represented by a plot of tablet tensile strength vs tablet porosity; while tablet ability is defined as a powdered material's capacity to withstand densification [21]. This phrase is proposed when all three variables are addressed in a single study. Although smaller particles formed by the breakage of larger particles may be rearranged further, the compaction process typically consists of particle rearrangement followed by pressure deformation.
Powder properties
The physico-technical qualities of pharmaceutical solids determine the performance and processing of solid dosage forms, particularly their compressibility. These attributes are interconnected, and changing one will almost certainly affect the others.
Surface properties
Powder materials' movement and intermolecular attraction are highly influenced by their surface properties. Depending on whether the atoms or ions are on a surface, the distribution of intermolecular and present within a particle differs. This is caused by unmet attractive molecular forces that extend a short distance beyond the solid surface. As a result, free surface energy of solids is formed, which is significant in interparticulate interaction [22]. Two types of particle attractive forces are cohesion between like particles and adhesion between unrelated particles. The attractive forces resist the differential movement of constituent particles when an external force is applied [23, 24]. Residual solvent on the surface of solid particles, electrostatic forces, and adsorbed moisture are all examples of relative particle movement resistance.
Porosity
The porosity of powder is defined as the ratio of
total void volume (Vv) to bulk volume (Vb) of a material (E). The full void
volume, Vv, is given by Vv= Vb – Vt, where Vt is the true volume.
1 - Vt / Vb = E= Vb - Vt / Vb = 1 - Vt / Vb
One of the ways used to determine the compressibility of a powder bed is the degree of volume drop owing to applied pressure, which is related to porosity and assumed to be a first-order reaction [25, 26]. The porosity–pressure relationship, which is often employed as a measure of compressibility, is also explained by the Heckel equation.
Flow characteristics
The flow feature of a pharmaceutical powder is crucial
for maintaining optimum die fill during compression, particularly in the direct
compaction process. A high number of particles, excess moisture, lubricants,
and electrostatic charge are all possible causes of poor powder flow. The
maximum angle between the plane of powder and the horizontal surface, which is
often used to analyse powder flow, is known as the angle of repose. A value of
less than 30 degrees implies free flowing material, a value of 40 degrees
offers fair flow potential, and a value of 50 degrees indicates difficult power
flow. A powder's cohesivity is related to its bulk density. Another way to
assess flowability is to examine the relationship between bulks and tap
density. The Hausner Ratio (H) and Carr's Index are calculated using the tapped
and bulk densities (CI) [27,28]. The Hausner ratio, which ranges from 1.2 for
free-flowing powders to 1.6 for cohesive powders, is the percentage of tapped
density to bulk density. Carr's Index is the ratio of the difference between
tapped density and bulk density to the tapped density, which is 100 times the
percentage compressibility. Carr's index values of 5–12% indicate free-flowing
powder, 23–35% indicate poor flow, and >40% indicate extremely awful flow
[29]. Flow rate is also utilized to determine particle resistance to movement,
especially in the case of granular powders with little cohesiveness. The
compressibility index, or I, is a simple measure of how easily a material may
flow. Vt is the tap volume, and V0 is the volume before tapping.
I = [1 - Vt/ V0] 100
Where, Vt is the tap volume, and V0 is the volume
before tapping. I value below 15% indicate good flow, whereas values above 25%
indicate poor flow. The state of consolidation of a powder is plotted as a
function of compaction pressure in a compaction equation [30]. Only a few
examples are porosity, volume (or relative volume), density, and void ratio.
Since Walker's recording of the first-ever accurate
compaction data in 1923, a number of compaction-related equations have been
given. The most often used equations are the Heckel and Kawakita equations,
which link the physical properties of the materials to applied pressure.
Kawakita equation
The Kawakita equation for powder compression is based
on the notion that at all phases of compression, the particles are subjected to
compressive load in equilibrium, resulting in a constant product of the
pressure and volume terms [31].
[1/ab + Pa/a] = Pa/C
[V0 - V/V0] = C
Where Pa is the applied axial pressure, an is the
particle bed's degree of volume reduction, and b is a constant that is said to
be inversely related to particle yield strength. V0 represents the initial
apparent volume of the powder, C represents the degree of volume reduction, V
represents the volume of the compact at pressure, and C represents the degree
of volume reduction [32, 33]. Soft fluffy pharmaceutical powders and low
pressures with high porosity work best with this equation.
Heckel equation
The Heckel model provides a mechanism for transforming
a parametric representation of force and displacement information to a linear
relationship for purely plastic materials. As a result, the Heckel model is the
most widely used connection because it provides a simple approach to measure
relative density and applied pressure. The Heckel equation is based on the
assumption that when bulk powder densification is forced, it follows
first-order kinetics.
The following is the Heckel equation:
KP + A = ln [1/1–D]
Where D is the relative density of the tablet at
pressure P, and K is the slope of the straight-line part of the Heckel plot.
The mean yield pressure, Py, is calculated by reciprocally transforming the
slope. In-die tablet thickness measurements determine the apparent mean yield
pressure, and the intercept of linear component A represents powder
densification as a result of initial particle rearrangement.
Walker equation
The Walker equation103 is a differential equation that
assumes that the rate of change of pressure in relation to volume is
proportional to the pressure. V0 is the volume at zero porosity, and Log P = –L
x V? / V0 + C1. V?/V0 = V = 1/D is the relative volume, and C1 is constant. The
pressing modulus is defined as the coefficient L [34].
Factors Influencing
Tableting speed (dwell time, lag time), particle
mechanism, amorphism, polymorphism, moisture content, and salt form. The solid
state of lubricants and their concentration, simultaneous processing of
excipients or medicines, the pre and main-compression force profile,
granulation techniques, and ultrasonic vibration all influence the compaction
of pharmaceutical powders [35].
Moisture content
Studying moisture adsorption and absorption by
excipients and solid dosage forms can aid in excipient selection, such as
disintegrating agents, direct compression carriers, and binders, as well as
determining humidity management requirements during manufacturing and storage.
Moisture affects the flow, mixing rheology, compaction, real density, and
mechanical properties of granules and tablets. Water–powder interaction is a
critical issue in the formulation, processing, and performance of solid dosage
forms since water is employed in every step of the production process. The
amount of water associated with a solid is determined by its chemical affinity,
surface area, and available sites of interaction at a certain RH and
temperature [36]. Moisture promotes the formation of interparticulate linkages
by enhancing the tensile strength of the powder bed and minimising density
fluctuations within the tablet. Moisture can also cause plastic deformation, as
well as a reduction in the elastic characteristics of powder materials [37,
38].
Compression force profile
The pace at which pharmaceutical powders are
compressed can have a major impact on their compaction properties. In order to
boost tablet strength and reduce the incidence of capping and lamination, it is
beneficial to change the manner of force application.
Solid-state properties
Drugs and excipients used in tablet production come in
a wide range of solid-state forms. Because these forms often differ in their
physico-technical behaviour, it's crucial to understand their impact on
compaction [39].
Hydration
When crystal hydrates are squeezed, the water of
crystallization is eliminated, resulting in weak tablets. This highlights the
importance of a sufficient moisture content in the development of strong
tablets [40].
Crystal habit
The crystal habit of isomorphic and non-isomorphic
drugs is the main distinction. The medicine's crystal habit can affect
tableting behavior, flowability, and the tendency to stick to the punches.
Crystal engineering and particle design can help to increase compactibility
[41].
Numerous pharmaceutical substance polymorphism forms
have been widely studied in terms of their physical and molecular
characteristics. Because of the existence of sliding planes, crystal plasticity
is characterized by greater fragmentation at low pressure, increased plastic
deformation at higher pressure, and lower elastic recovery. In a study of
compression behaviour of pure orthorhombic or monoclinic paracetamol,
orthorhombic crystals showed excellent technical properties, avoiding capping
even at high compression pressures [42]. The complete lack of long-range,
three-dimensional intermolecular order in amorphous materials can significantly
alter the mechanical properties of a powdered amorphous pharmaceutical
molecule. The enhanced compaction behaviour of amorphous materials may be owing
to higher plastic deformation than crystalline equivalents [43].
Particle size and particle size distribution have an
impact on both the particle rearrangement and compaction stages. Average
particle size and tablet tensile strength correlations are crucial for
selecting and creating appropriately sized particles. While the size
distribution of free-flowing particles is not critical for tablet porosity, it
can have a significant impact on tablet tensile strength due to post-compaction
hardening, according to the researchers [44,45].
Due to poor flowability and compaction behaviour,
pharmaceutical powders are commonly granulated prior to tablet manufacture. The
optimum granulation process is chosen for the production of porous and
free-flowing granules, enabling for the manufacture of tablets with good
mechanical strength at low compression pressures. The order of tensile strength
in wet granulation was wet granulation on a fluidized bed > wet granulation
in a tumbling fluidized bed > wet granulation in a high-speed mixer. The
order of tensile strength in melt granulation was melt fluidized bed
granulation > melt tumbling fluidized bed granulation > granulation and
melt high-speed mixer granulation [46, 47]. According to these data, granule
compactabilities varied depending on the granulation procedure used.
The most prevalent compression-related tablet concerns
are capping/lamination and sticking/picking. The separation of a tablet's top
or bottom crown from the main body is referred to as capping, whereas the
separation of a tablet into two or more layers is referred to as lamination.
These tableting difficulties usually appear shortly after compaction, however
they can also grow over time. A friability test is the most efficient way to
test such a problem [48]. The fundamental cause of these problems is materials'
inability to alleviate tension after force decrease. By trapping air in the
tablet, excess particles can also induce capping and lamination [49]. The
intrinsic deformation properties of the material, such as plastic, brittleness,
or elasticity, can play a role in tableting concerns. Elastic recovery is
regarded to be the most likely cause of capping in high-density zones in a
compact bed, when density and stress are unevenly distributed [50]. Tablet
capping and lamination difficulties are also linked to pre and primary
compaction characteristics. Pre-compression, a slower tableting speed (a longer
dwell time), and a lower final compression force may all help to eliminate
capping/lamination problems. The type of tools used can have an impact on
capping and laminating [51]. Deep concave punches usually produce capping
because the cap region endures more radial expansion and shear stress than the
tablet's body. Flat punches produce reduced shear stress within a compact. Dies
produce a wear ring in compression areas, and the squeezed tablets have fewer
diameters to pass through the die wall, resulting in capping and/or lamination
upon ejection [52]. Picking is the process of removing surface material from a
tablet with a punch. Picking is often associated with punching, engraving, or
embossing. To address this problem, lettering should be made as large as
feasible, or a larger tablet can be created [53]. Sticking is the process of
attaching tablet material to the die wall. Sticking is affected by the surface
roughness of the punch, the compaction force, and the mix composition. At low
compaction forces, punch face chrome plating enhances sticking, while at higher
compaction forces, it reduces it. Sticking and picking have been connected to
increased moisture, therefore keeping an eye on the moisture level is also
important for treating these concerns [54].
Compressibility is an issue with many pharmaceuticals
and excipients. Depending on what makes up the majority of the mix, either the
API or the excipient's compaction behaviour should be refined (s). Additional
treatments such as granulation and coprocessing may be necessary to achieve
adequate compactibility [55]. Low-dose medicines with weak compressibility
rarely have tableting concerns since excipients contribute the required
compressibility. In the case of high-dose drugs, however, enhancing the API and/or
selecting the appropriate excipients, particularly diluents and binders, is
critical to decreasing tableting difficulties [56].
API modification
Due to the limited role of excipients in enhancing
compactibility, API modification is required for high-dose drugs, even if it is
not allowed [57].
Excipient modification/selection
The type and amount of excipient(s) utilized has an
effect on the overall quality of the tablets. Excipients are classified into
two groups based on how they aid in compaction. Diluents and binders, for
example, have a beneficial impact; disintegrants and lubricants, on the other
hand, have a negative impact.
Diluent
Diluents are the most important excipients since they
are often present in higher concentrations than other excipients.
Compressibility of diluents ranges from extremely compressible materials like
MCC to extremely low compressible materials like starch. As previously
indicated, the main behavioural patterns of medications during compaction are
plastic deformation, elastic deformation, and brittle breakage. MCC and
amorphous binders, which are capable of plastic deformation, have a higher
number of attractive forces, resulting in improved compact strength [58]. The
rough surface of the particles actively adds to compact strength even in the
absence of fragmentation. The compression properties of the API and excipients
point to an ideal balance of brittle fracture and plastic behaviour, which is
necessary for effective tablet manufacturing. The most commonly used excipients,
in order of brittleness, are MCC, spray-dried lactose, -lactose, -lactose
monohydrate, and DCP [59].
Lubricants
Lubricants like other types of pharmaceutical
excipients, are employed in the formulation of solid dosage forms to aid in
production and ensure that the finished products are of acceptable quality.
Lubricant is best characterized as a suitable material that, when a tiny amount
of it is applied between two rubbing surfaces, lowers friction at the contact.
Metallic stearates, stearic acid, talc, and waxes are often used lubricants, as
are water soluble substances such as boric acid, sodium benzoate, sodium
acetate, sodium chloride, leucine, carbowax, sodium oleate, and sodium lauryl
sulphate [60]. Establishing an ejection profile for each lubricant to alleviate
stresses associated with tablet compaction is crucial for minimizing dissolving
and tensile strength concerns in formulations [61].
Disintegrants
In order to achieve the appropriate dissolving rate of
drug substance(s) from a tablet, the tablet's cohesive strength must be
overcome and the tablet broken down into fundamental particles. To do this,
disintegrants are utilized in formulations. Carbohydrates such as starch (3–15
percent), MCC (5–15 percent), pregelatinized starch (5–10 percent),
croscarmellose sodium (1–5 percent), sodium starch glycolate (2–8 percent), and
cross-povidone (2–5 percent) are among the most commonly used disintegrants
[62]. The fundamental mechanism of disintegration is swelling in the presence
of water. Certain materials' tendency to absorb moisture from their
surroundings and swell as a result, lowering tensile strength. Many commonly
used diluents, such as microcrystalline starch (MCC) and starch, are
disintegrants. MCC has a high compressibility, while starch has a low
compressibility and affects compact tensile strength. Because
super-disintegrants such sodium starch glycolate, cross-povidone, and
croscarmellose sodium work at a lower concentration, they are less likely to
impact the blend's compaction behavior [63]. However, sodium starch glycolate
in quantities more than 10% is known to reduce tablet tensile strength due to
its low compressibility. The concentration of disintegrants must be optimized
to avoid a negative impact on the compressibility of the tablet blend.
Granulating agents/binders
To turn powder into granules, granulating agents are
utilized. Water and organic solvents operate as granulating agents by partially
dissolving the surface of the particles and forming solid bridges during
evaporation. On the other hand, these types of connections are weak and result
in the formation of friable granules [64]. As a result, adding a binder to
granulations to increase granule strength and avoid capping and lamination is
typical practice. Granulating agents are hydrophilic, cohesive polymers that
help in granulation and provide strength after drying. Because bonds are broken
as the compaction pressure is released, a binder that promotes flexibility may
lower tablet strength [65]. As a result, choosing a good binder for a tablet
formulation needs a detailed grasp of binder properties for boosting tablet
strength as well as interactions between the tablet's numerous constituents.
Compaction is a critical step in the creation of
tablets, and understanding the physics behind it is critical. Because the
intrinsic deformation behaviour of drugs/excipients, as well as process
conditions, are known to alter variables such as solid-state characteristics,
the end product is known to be affected. Despite the advances in tablet
technology, a thorough grasp of compaction physics remains elusive.
Understanding compaction profiles such as force-time profiles, force
displacement profiles, and pressure–porosity correlations can help
pharmaceutical chemists comprehend process dynamics and produce ideal
formulations free of capping, lamination, picking, and sticking. If the
compaction behaviour of the tablet matrix and individual excipients are
researched, excipient selection can be based on science. Optimizing process and
product parameters that affect the compaction process may also help achieve
sufficient tensile strength and needed biopharmaceutical properties in tablet
medicinal products.
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material
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Authors' contributions
All the authors have contributed to the research work
and preparation of the final manuscript.
Conflict of interests
The authors declare no conflict of interests.
Acknowledgments
No acknowledgments
Ethical declaration
No animal or human subjects were used during the
preparation of this manuscript.
Funding
No