Official: Á1062Ñ Tablet Compression Characterization
Official: Á1062Ñ Tablet Compression Characterization
Printed by: Rock Pharma Official Date: Official as of 01-Dec-2017 Document Type: GENERAL CHAPTER @2022 USPC
DOI Ref: a7x5u DOI: https://doi.org/10.31003/USPNF_M99395_02_01
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12. TABLET COMPRESSION PROFILE
13. MACHINE SPEED SENSITIVITY
14. CONCLUSIONS AND RECOMMENDATIONS
GLOSSARY
REFERENCES
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1. BACKGROUND
The tablet is currently the most widely used dosage form for oral drug delivery (see Pharmaceutical Dosage Forms á1151ñ).
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The advantages of the tablet include economy of manufacture, patient convenience, and compliance. Tablets may also offer
additional advantages over other dosage forms, such as superior physical or chemical stability.
Powder compression is a critical process in manufacturing the tablet dosage form. Although this process has been used
routinely for over a century, problems related to powder compression in pharmaceutical formulation development and
manufacturing persist. Common problems include tablet failures, such as capping and lamination (1–3), high friability, powder
sticking to punch surfaces or the die wall, and insufficient mechanical strength to withstand stress in downstream processing.
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Some formulations may exhibit acceptable compression characteristics during early development where production volumes
are usually low but become problematic during scale-up.
The properties of compressed tablets are sensitive to both material characteristics and process parameters. The characteristics
of the equipment used and the ambient conditions of temperature and humidity are also key factors that influence tablet
compression. Physical properties such as particle size (4), particle shape (5,6), surface texture (7), crystallinity, and moisture
content (8) influence powder tableting performance by affecting the bonding strength and/or the bonding area (9,10). The
powdered material mechanical properties, such as particle hardness, elastic properties, viscoelastic properties, plasticity, and
particle brittleness, also affect tablet strength (11–13). The extent of lubrication is yet another important factor that affects
powder compression. A lubricant is typically added to the drug product blend formulation as a final step prior to compression
to reduce frictional forces during compression and tablet ejection. This added lubricant, however, may adversely impact tablet
mechanical strength and dissolution release rate.
This chapter describes the current understanding of this specialized area and outlines experimental methodologies for
characterization of tablet compression to provide guidance for standardized compression test procedures and use of
terminology. Although the fundamental concepts described here are also applicable to other processes, such as plug formation
during encapsulation and roller compaction, the focus of this article is on tableting.
[NOTE—The Glossary defines terms with the International System of Units (SI), commonly used in pharmaceutical tablet
compression.]
2. COMPRESSION PHASES
Powder compression behavior is governed by the physical and mechanical properties of the material as well as aspects of
the compression process such as pressure (i.e., stress), degree of deformation (i.e., strain), and rate of deformation (i.e., strain
rate). Therefore, knowledge of stress, strain, and strain rate is important for understanding powder behavior during the
compression process. The majority of pharmaceutical tablets are manufactured by “uniaxial powder compression”. That is, each
tablet is formed by the densification of a loosely packed powder sample confined within a rigid die using two rigid punches
that approach from above and below (in a vertical plane). This tablet formation process is often described as occurring in four
stages, as shown in Figure 1:
1. Particle rearrangement
2. Compression
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DOI Ref: a7x5u DOI: https://doi.org/10.31003/USPNF_M99395_02_01
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3. Decompression
4. Ejection
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Figure 1. Stages of powder compression (lower punch pressure).
In the first stage, Particle rearrangement, particles typically change positions through slippage, rotation, or translational
movement, thereby reducing or eliminating pores in the powder without significant irreversible deformation. At the end of the
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first stage, where the particles have reached their fullest extent of rearrangement, the powder is usually significantly denser
than the starting powder because of reduced pore volume. Any further reduction in compact volume would require particle
deformation.
During the second stage, Compression, particles are deformed at points of contact with other particles, the die wall, or the
punch surfaces. During this stage, compression pressure often increases rapidly, causing volume reduction as the powder density
increases. Under pressure, particles initially undergo elastic deformation. Depending on mechanical properties and stress at
points of contact, particles can subsequently undergo varying degrees of fragmentation and/or plastic deformation. If
fragmentation takes place early in the second stage, some of the fragments may undergo further rearrangement. However,
relative particle movement is limited when the powder is highly consolidated. For most pharmaceutical materials, plastic
deformation is an important part of the compression process that leads to an increase in the area of contact between particles,
contributing to higher compact strength. Clean particle surfaces generated from fragmentation also contribute to higher
compact strength. The deformation behavior and resultant tablet mechanical properties of many pharmaceutical powders are
also sensitive to the compression speed (punch velocity) and the length of time at which the powder is held under pressure
at a constant volume (dwell time). Tablet density and tensile strength of speed-sensitive powders (such as starch) depend on
tableting speed, with higher speeds (i.e., shorter dwell times) generally producing less-dense tablets with lower strength. The
end of the second stage is usually the time of highest compression pressure.
During the third stage, Decompression, the punches retract, resulting in a decreasing axial punch pressure. As axial pressure
is reduced to zero during decompression, residual die wall pressure typically exists in the radial direction. During this phase,
particles primarily undergo elastic recovery, depending on both the pressure and the mechanical properties of the particles.
Elastic recovery may provide insight into the elastic deformation that the powder experienced during compression. Excessive
elastic recovery may reduce the interparticle bonding and can result in a significant decrease in tablet mechanical strength.
These same three stages apply to a pre-compression step in tablet manufacturing, which often involves a lower compression
pressure and may be added as a precursor to the main compression step.
During the fourth stage, Ejection, the tablet is typically pushed out of the die by the lower punch. As the tablet emerges from
the die, the ejected portion of the tablet is free to expand radially due to elastic recovery (i.e., release of residual die wall pressure).
Significant shear stress may develop within the tablet and at the edges of the tablet–die interface because the lower portion of
the tablet remains constrained by the die wall. In severe cases, this shear stress can result in tablet lamination or capping. The
formation of a dense and defect-free compact depends on the ability of the particles to form interparticulate bonds during
compression, and the ability of these bonds to withstand elastic expansion during the decompression and ejection phases.
Tooling shape and size may also affect the properties of the compressed tablet because they affect density and stress distribution
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DOI Ref: a7x5u DOI: https://doi.org/10.31003/USPNF_M99395_02_01
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during compression. The thermodynamics of the compression process, e.g., via compression calorimetry (14,15), is another
important aspect of powder compression, and it can be studied using instrumented presses (see 3. Tablet Compression
Characterization Equipment).
Various compression methods have been used to characterize the compression properties of pharmaceutical powders. Each
method has benefits and limitations. To characterize powder-compression properties, a compression pressure (stress) is applied
to a powder to produce a coherent, compacted specimen or tablet. The loading system used to apply the compression pressure
may have several designs. Typical compression instruments used in the pharmaceutical industry include hydraulic presses,
instrumented research tablet presses, tablet press emulators, compaction simulators, and instrumented production tablet
presses.
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3.2 Instrumented Research Tablet Press
Research tablet presses have two basic designs: eccentric single-station and rotary multi-station presses. Eccentric
single-station presses typically are mechanically driven and compress the tablet using the upper punch with a sinusoidal position
profile; the lower punch is typically fixed during the compression cycle. Research rotary multi-station tablet presses are
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scaled-down versions of production-scale presses, and they compress tablets via the movement of both the upper and lower
punch as they pass under a pair of compression rolls. The geometry of the punch head (i.e., curvature and flat area) also
influences the shape of the punch position profile on a rotary tablet press.
4. TOOLING
Tablets can be manufactured with a variety of tooling sizes and shapes. Commonly used tooling shapes for basic material
characterization are flat-faced, flat-faced with beveled edge, and standard round concave tooling that produces convex-shaped
tablets. A wide variety of tooling shapes may be used in the production of pharmaceutical products, based on technical and
commercial considerations (16). Tooling may be embossed (i.e., raised markings on punch surface), thus introducing debossed
markings on the compressed tablets. Depending on the powder compression properties and manufacturing process parameters,
the tablet tooling design may affect the tablet mechanical integrity.
Tablet compression equipment can be used to produce a variety of punch displacement–time profiles. Figure 2 is an
illustration of three of the simplest profiles used for fundamental material characterization.
The properties of a compressed powder are dependent upon several factors, including compression pressure, compression
speed, and the compression profile. Compression experiments may be performed with one moving punch and one stationary
punch; one moving upper punch and a fixed base (i.e., no lower punch); or two independently moving upper and lower
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punches (double-sided compression). Because the compression set-up and parameters can affect measured compact properties,
it is important to specify the experimental details when reporting results. Typical compression profiles include:
• Linear compression and decompression phases that yield saw-tooth punch displacement–time profiles (Figure 2A)
• Square punch displacement–time profiles (Figure 2B)
• Modified sinusoidal punch displacement–time profiles typical of a rotary tablet press (Figure 2C)
Either one punch (single-sided compression) or both punches (double-sided compression) may follow these profiles. Accurate
measurements of the displacement–time profiles, as well as the resultant forces applied, require high-accuracy instrumentation,
and in some cases correction for system deformation (i.e., elastic deformation of punches and other machine components).
Punch displacement–time profiles for most production-scale tableting machines are a combination of the sinusoidal and square
profiles, where the compression and decompression phases follow the sinusoidal profile and between them there is a flat portion
representing the dwell time.
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DOI Ref: a7x5u DOI: https://doi.org/10.31003/USPNF_M99395_02_01
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Figure 2. Punch displacement–time profiles: A) saw-tooth profile, B) square profile, and C) modified sinusoidal profile. Only
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one curve for punch displacement over time is represented (e.g., upper-punch movement).
Tablet strength is primarily influenced by the particle–particle bond strength and true areas of contact (e.g., surface area
over which attractive force between particles is significant) (17). When particle surfaces are brought into close proximity,
interparticle interactions (e.g., van der Waals forces) are maximized and typically lead to strong interparticle bonding. Tablet
mechanical strength can be quantified by measuring the maximum stress, either compressive or tensile, that a tablet can sustain
prior to failure (breaking). A commonly used test is to place tablets between two platens and measure the force necessary to
fracture the tablets; this test is described in Tablet Breaking Force á1217ñ. For conventional round tablets with a circular
cross-section, loading occurs across the diameter of the tablet and is sometimes referred to as “diametral loading”. Other
methods, such as three-point or four-point bending tests, are also available but are less frequently used in production settings
because they can require more complex equipment and analysis. Tablet strength, as determined by these tests, is often referred
to in the pharmaceutical industry as “hardness”, although a more exact term is “breaking force”. In material science, hardness
refers to the resistance of a surface to penetration or indentation (e.g., Mohs hardness, indentation hardness, or permanent
deformation pressure). The tablet breaking force value serves as both a criterion by which to guide product development and a
quality control specification.
Tablet strength can be affected by several factors including:
• Tablet size and shape: Because breaking force is affected by tablet size and shape, a more reliable parameter for quantifying
mechanical strength of a tablet is tensile strength. For cylindrical or convex tablets with simple shapes, tensile strength
may be calculated from the diametral test, described in á1217ñ.
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• Relative density: Tablet strength increases as powders are compressed to a higher relative density.
• Time and storage conditions: Tablets can relax or be influenced by environmental conditions (e.g., relative humidity),
therefore tablet storage conditions and length of storage time before testing should be specified for reproducible strength
determinations.
• Formulation composition and manufacturing process: Each component has unique mechanical properties, and in some
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cases these properties can impact the mechanical properties of other components. For example, incorporation of a
lubricant, which is meant to reduce adherence to manufacturing equipment, can reduce interparticulate bonds. Problems
in manufacturing processes, such as over-mixing or over-granulation, also can influence tablet strength.
Tablet performance attributes, such as disintegration, dissolution, and friability, may be affected by tablet compression and
may also be reflected in the tablet mechanical strength. Typically, a tablet of lower strength will have faster disintegration and
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dissolution as well as higher friability (see Tablet Friability á1216ñ).
Virtually all pharmaceutical compacts contain porous regions (pores). Tablet porosity is a measure of the volume of the tablet
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that consists of pores, or “void space”. It is critically important to consider tablet porosity when quantitatively characterizing
tableting properties, because it has a substantial effect on measured compact properties. Tablet solid fraction, also referred to
as relative density, is a measure of the volume of solid material in a compact and may be calculated using Equation 1. Tablet
solid fraction and porosity are related, as shown in Equation 2. The true density of a material is the average mass/unit volume
(e.g., g/cm3) exclusive of all voids (see Density of Solids á699ñ). Typical true densities of organic powders of pharmaceutical
interest are in the range of 1.0–1.7 g/cm3, whereas inorganic ingredients may be in the range of 2.0–3.0 g/cm3 (18,19).
Simple tablet geometries (e.g., round flat-faced) are often used for research purposes, to simplify the determination of tablet
volume by using the measurement of tablet dimensions. For more complex tablet shapes, alternative methods of determining
tablet volume, such as the use of instruments that quantify envelope volume, may be used. Typical pharmaceutical tablets have
porosities between 0.1 and 0.4, depending on the material properties and the conditions used to produce the tablet (20). A
porosity of 0 would correspond to a theoretical tablet mass in which all pores had been eliminated, resulting in a compact
consisting entirely of solid material (i.e., solid fraction = 1). With increasing compression pressure, pores are eliminated through
particle rearrangement and deformation, and the tablet porosity decreases unless extensive elastic recovery of the tablet after
decompression causes cracks or other defects in the tablet.
8. MANUFACTURABILITY PROFILE
Tablet breaking force is often measured as a function of compression force. A plot of breaking force versus compression force
is useful for monitoring changes in the tableting behavior of a powder with a fixed tablet size, shape, and weight produced
under similar compression conditions (i.e., production speed and force), such as those obtained using a specific rotary tablet
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press. In this case, the relationship between tablet breaking force and compression force may be termed “manufacturability”,
because it is often the criterion used in a production setting to monitor tablet compression. See Figure 3 for an example of a
manufacturability profile.
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9. TABLETABILITY PROFILE
Although valuable in a manufacturing setting, tablet breaking force should be replaced with tablet tensile strength for
quantifying tablet mechanical strength (see á1217ñ), and compression force should be replaced with compression pressure
(compression force per unit area of the punch tip cross-section). These changes will minimize the impact of tablet size, thickness,
and weight on compression data analysis. The relationship between tablet tensile strength and compression pressure is termed
“tabletability”. Tablet tensile strength usually increases initially with increasing compression pressure. Depending on tablet
composition, tensile strength can either continue to increase or gradually level off at higher pressures. It is also possible that
the tablet tensile strength may decrease with increasing pressure, a phenomenon known as overcompression. This decrease in
tablet strength with increasing pressure is most often the result of tablet defects of some materials that occur at higher
compression pressures. Because of the diversity of powder tabletability behaviors, it is beneficial to determine the tensile strength
of tablets prepared under a range of compression pressures, instead of a single pressure, if possible. This will help obtain an
accurate characterization of powder tabletability. When the available resources or materials are limited, the compression
pressure required to make a compact at a specified tensile strength (e.g., 1 MPa) can be used to compare compression properties
of different powders. The tabletability of pharmaceutical materials can often be described by Equation 3 for a typical range of
compression pressures, where K and B are empirical constants:
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Compressibility is the dependence of tablet solid fraction (or porosity) on compression pressure. The compressibility curve
can be obtained by plotting tablet solid fraction as a function of compression pressure. See Figure 5 for an example of a
compressibility profile.
For many pharmaceutical materials, Equation 4 can be used to describe compressibility over a typical range of tablet solid
fractions, where a and b are empirical constants:
The compression pressure necessary to form a compact with a specified solid fraction (e.g., 0.85) may be used to compare
diverse pharmaceutical materials. Use of 0.85 as a reference solid fraction is convenient because many, although not all,
pharmaceutical powders can be compressed to this solid fraction, and a reference solid fraction enables comparative
assessments of tablet property measurements. Alternative values for the reference solid fraction may be used as needed.
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Compressibility has also been described using the Heckel equation (Equation 5), which predicts a linear dependence of the
logarithm of tablet porosity versus compression pressure. In Equation 5, K and B are empirical constants.
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However, the Heckel equation is overly simplistic in that it does not adequately describe powder compressibility in the
low-pressure region, where ln(porosity) versus pressure data are not linear. More sophisticated models, such as the modified
Heckel equation (21) and the Drucker-Prager Cap Model (22), have proven to be more reliable in describing powder
compressibility to account for the transition between the state of a powder and the state of a tablet.
The relationship between tensile strength and solid fraction (or porosity) is termed “compactibility”. Generally, tablet tensile
strength increases exponentially with increasing solid fraction, and powder compactibility is often well described by the
Ryshkewitch-Duckworth equation (Equation 6) where k and A are empirical constants (23):
This relationship is qualitatively reasonable, as the presence of more or larger pores in a compact weakens it. Moreover, this
relationship highlights the importance of determining tablet porosity to gain a better understanding of powder tableting
performance. For example, when a low tablet tensile strength is associated with high porosity (solid fraction), an effective
strategy for overcoming the tableting problem is to add a more highly deformable excipient, which increases the plasticity of
the powder and decreases tablet porosity. See Figure 6 for an example of a compactibility profile.
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Figure 7 illustrates the relationships among tensile strength, compression pressure, and solid fraction (or porosity) and related
tableting parameters. The relationships among tensile strength, compression pressure, and solid fraction (or porosity) can be
presented in three dimensions as shown in Figure 8, where the three faces of the three-dimensional plot represent the
tabletability, compressibility, and compactibility (24).
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Figure 7. Relationships among tableting parameters for compression data analysis.
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The effect of compression speed may be assessed by comparing the properties of compacts that were prepared at different
compression speeds. A range of compression speeds can be obtained by using a hydraulic press, a rotary tablet press, or a
compaction simulator. For fundamental material assessments, tablet properties such as tensile strength, hardness, and porosity
can be used to quantify strain rate sensitivity (SRS) of a powder using Equation 7.
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Tablet compression is a complex process dependent on the drug product composition, material properties, manufacturing
process parameters, environment conditions, equipment, and tooling design. To gain an in-depth understanding of the
compression behavior of a powder, it is beneficial to have knowledge of the particle size and shape, solid form, and water
content of the powder. Without appropriate control and descriptions of these factors, the data obtained are not meaningful
for accurately characterizing tablet compression properties of a powder. Therefore, these properties should always be considered
during the analysis of the tablet compression results. Table 1 shows examples of parameters that are commonly used in the
characterization of the compression properties of pharmaceutical solids.
Punch displacement–time profile Specify Saw tooth, square, sinusoidal; single-sided, double-sided
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Tablet properties (weight,
dimensions) Specify Tablet thickness, tablet diameter
Data Analysis
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Compressibility Compression pressure (σC) at specified solid fraction (SF)
SRS = (P2 − P1)/P2, P2 = mean yield pressure at 300 mm/s; P1 = mean yield pressure at
SRS Specify 0.033 mm/s, saw-tooth punch displacement–time profile
a These examples are not required and they may not be suitable for all materials. They should not be viewed as prescribed values for characterizing powders.
GLOSSARY
Breaking force: The force [in Newtons (N)] required to cause tablet mechanical failure. Often referred to as tablet
hardness (see á1217ñ).
Brittleness: The property that leads to particle or compact fracture, typically very rapidly.
Capping: Laminar splitting along the edge of the crown or band of a compressed tablet.
Compactibility: The ability of a powder to form an intact compact with measurable strength.
Compactibility profile: Change in tensile strength of a compressed body with solid fraction (or porosity).
Compaction: The transformation of a powder into an intact compact with measurable strength and defined shape by the
application of compression pressure. Usually used synonymously with consolidation.
Compaction emulator: A device that physically approximates tablet press configurations where compression parameters
may be applied; parameters may include pre-compression and compression roll dimensions, tableting speed, ejection angle,
and punch design.
Compaction simulator: A device that permits powder compression, typically using a hydraulic source to control
displacement of punches that may be designed to match the force displacement profile of a high-speed press by means of a
computer.
Compressibility: The ability of a powder to be compressed (reduced in volume) by the application of stress.
Compressibility profile: Change in solid fraction (or porosity) of a compressed body with applied pressure.
Compression: The reduction in volume of a powder bed due to the application of a stress, e.g., loading.
Compression force: Force applied to compress a powder bed. The unit kN is commonly used in tableting.
Compression pressure: Pressure (force/area, in MPa) applied to specimen material; sometimes used interchangeably with
the terms “compaction pressure” or “compression stress”. See Compaction and Compression.
Compression profile: The relationship between Compression pressure, Solid fraction (or porosity), and tensile strength.
Dwell time: Duration of time (in ms) that the compression roll is in contact with the flat portion of the punch head. Often
used to describe rotary compression processes with a modified sinusoidal punch displacement–time profile.
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DOI Ref: a7x5u DOI: https://doi.org/10.31003/USPNF_M99395_02_01
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Elastic deformation: The change in shape of a stressed body that is completely recovered when stress is released. This is
time-independent, recoverable deformation.
Elastic limit: The amount of stress at which a material deviates from linear elastic behavior, i.e., the smallest stress that
leaves a detectable permanent deformation when unloaded.
Failure: The permanent collapse, breaking, or deforming of the material.
Force: A push or pull (in N) resulting from the interactions between two objects.
Hardness: See Breaking force.
Hydraulic press: A device that uses liquid pressure to enable the application of force to a specimen.
Indention hardness: The resistance of a surface to permanent deformation (indentation) when subjected to pressure by a
hard object.
Lamination: Condition in which a tablet splits or separates into layers.
Manufacturability profile: Change in breaking strength of a compressed body with applied force.
Mechanical properties: The characteristics of a material upon application of a stress. Examples include tensile strength,
yield strength, plasticity, brittleness, hardness, elastic modulus, and bendability.
Plastic deformation: The permanent change in shape of a solid body, without fracture, resulting from the application of
sustained stress beyond the elastic limit. Deformation occurs without a change in particle volume.
Plasticity: See Plastic deformation.
Pressure: Force applied to a unit area (in MPa), used interchangeably in this chapter with stress.
Porosity or void fraction: A measure of the empty spaces in a material. This is the fraction of the voids divided by the
total volume. Porosity ranges between 0 and 1, or as a percentage between 0% and 100%.
Shear stress: The force per unit area (in MPa) acting along a plane through a body.
Solid fraction: The apparent density divided by the absolute density of the solid, sometimes referred to as relative density.
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Solid fraction = (1 − porosity).
Sticking: The adherence of material to the faces of tablet press punches or dies after compression.
Stress: Normal stress. Used interchangeably in this chapter with pressure. See Pressure.
Tabletability profile: Change in tensile strength of a compressed body with applied pressure.
Tablet press: A mechanical device that compresses powder into tablets of desired size and weight.
True density: The average mass per unit volume, exclusive of all voids that are not a fundamental part of the molecular
packing arrangement.
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Viscoelastic deformation: Time-dependent partially recoverable deformation.
Yield strength: The stress needed to produce a specified amount of plastic deformation (usually a 0.2% change in length).
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Printed by: Rock Pharma Official Date: Official as of 01-Dec-2017 Document Type: GENERAL CHAPTER @2022 USPC
DOI Ref: a7x5u DOI: https://doi.org/10.31003/USPNF_M99395_02_01
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