Compression Physics in The Formulation Development
Compression Physics in The Formulation Development
Referee: Dr. Changquan Sun, Amgen, One Amgen Center Drive, MS 21-2-A,
Thousand Oaks, CA 91320-1799
0743-4863/05/$35.00 1
© 2006 by Begell House, Inc. www.begellhouse.com
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
S. PATEL, A.M. KAUSHAL, & A.K. BANSAL
I. INTRODUCTION
The use of pills and powders to administer drugs was reported as early as 1550
BC in Papyrus Ebers. The pill continued to be one of the most common dosage
forms until the middle of the 20th century, when mass-production of tablets
was introduced by the pharmaceutical industry following the invention of the
tableting machine, patented in 1843 by William Brockedon.1 Pharmaceutical
products have historically been administered to the body using a relatively basic
drug and excipient combination in suitable dosage form, usually resulting in
rapid release and systemic absorption of the drug(s). Different delivery tech-
nologies and routes of administration have been used to ensure optimal admini-
stration of therapeutic agents. All along the history of pharmacy, oral route has
been the most preferred way of drug administration and oral solid dosage forms
have been widely used mainly because of their convenience of administration,
ease of manufacturing, accurate dosing, and patient compliance.2,3 Out of pow-
ders, granules, pellets, tablets, and capsules, tablets have been the dosage form
of first choice in the development of new drug entities4 and account for some
70–80% of all pharmaceutical preparations.2,5 A flow-chart of the relationship
between solid pharmaceutical dosage forms is shown in Figure 1.
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
COMPRESSION PHYSICS IN THE FORMULATION DEVELOPMENT
Immediate release
• Spatial release
Controlled release
• Temporal release
Tablets can be made directly from powders, granules, pellets, or film coated
multiple units. The prerequisite, however, is that the material must have good
compressibility to form a tablet.6 In general, the tableting process involves, ap-
plying pressure to a powder bed, thereby compressing it into a coherent com-
pact.7 The simplest process for tableting is direct compression, in which the
drug(s) and excipient(s) are dry mixed and then compacted. For this process to
be successful, the powder mixture requires certain properties, such as high
flowability, low segregation tendency, and high compactibility. Pharmaceutical
powders often lack these properties and must, therefore, be pretreated with a
particle modification process before compaction.3 Generally, this pretreatment
is a granulation step in which the primary drug(s) and the excipient particles are
agglomerated into larger secondary particles (granules or agglomerates), usually
of a higher porosity than the primary ones. Techniques to improve tabletability
involve different granulation techniques, both wet and dry, and special wet
granulation techniques, which yields almost spherical agglomerates, such as pel-
letization, or extrusion–spheronization.8
Compaction represents one of the most important unit operations in the
pharmaceutical industry because physical and mechanical properties of the tab-
lets, such as density or strength (hardness/friability), are determined during this
process. Dosage form integrity and bioavailability is related to the tablet com-
pression process. The production of compressed tablets is a complex process
involving many variables and a number of engineering principles and the com-
plete understanding of the physics of compression has been an ongoing proc-
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
S. PATEL, A.M. KAUSHAL, & A.K. BANSAL
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
COMPRESSION PHYSICS IN THE FORMULATION DEVELOPMENT
II.B. Porosity
The porosity of powder (E) is defined as the ratio of total void volume (Vv) to
the bulk volume (Vb) of the material.4 The total void volume, Vv is given by Vv
= Vb - Vt where, Vt is the true volume.
E = Vb - Vt / Vb = 1 - Vt / Vb (1)
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
S. PATEL, A.M. KAUSHAL, & A.K. BANSAL
The percentage compressibility, also called as Carr’s Index29 is 100 times the
ratio of the difference between tapped density and bulk density to the tapped
density. Values of Carr’s index of about 5–12% indicate free-flowing powder,
23–35% indicate poor flow, and >40% an extremely poor flow.27
Additionally, flow rate is used to determine the resistance to movement of
particles especially for granular powder with poor cohesiveness. A simple indi-
cation of the ease with which a material can be induced to flow is given by
compressibility index, I.
where, Vt is the tap volume and V0 is the volume before tapping. Value of I be-
low 15% indicate good flow properties but values above 25% mean poor flow.6
II.D. Compaction
Compaction can be defined as the compression and consolidation of a particulate
solid–gas system as a result of an applied force.30 Compression involves a reduc-
tion in bulk volume as a result of reduced gaseous phase. A closer packing of
the powder particles as a result of rearrangement is the main mechanism for ini-
tial volume reduction. As the force is further increased, rearrangement becomes
difficult and particle deformation sets in. Consolidation, which is a subsequent
process, involves increase in the mechanical strength resulting from particle–
particle interactions. As the particles move into closer proximity to each other
during the volume reduction process, bonds are established between the parti-
cles. The nature of bonds formed is similar to those of the molecular structure
of the interior of the particles, but because of the roughness of the particles sur-
face, the actual surface area involved is small. Consolidation is the major reason
for increase in mechanical strength of a powder bed, when subjected to rising
compressive forces.6 The various steps involved in powder compaction are il-
lustrated in Figure 2.
Over the years, there has been considerable confusion in literature around
tableting terminology. Different terms, e.g., compressibility, compactibility, and ta-
bletability, have been used by different authors to describe the same type of rela-
tionship. The root cause of this confusion is that three variables, pressure,
tablet tensile strength, and porosity, are not always studied simultaneously and
the first systematic study of all three variables and definition of the terms was
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
COMPRESSION PHYSICS IN THE FORMULATION DEVELOPMENT
Particles
Undergo rearrangement to
Solid
form a less porous structure
bridges
Intermolecular force
Fragmentation Deformation Bonding (distance attraction
forces)
FI GURE 2 . The various st eps involved in com pact ion of powders under
an applied force.
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
S. PATEL, A.M. KAUSHAL, & A.K. BANSAL
2. Deformation of Particles
As the upper punch penetrates the die containing the powder bed, initially there
are essentially only points of contact between the particles. Application of the
external forces to the bed results in force being transmitted in through these in-
terparticulate points of contact, leading to development of stress and local de-
formation of the particles. Energy is lost at this stage as a result of interparticu-
late and the die-wall friction, as well as deformation. Based on their mechanical
properties, powders are classified as plastic, elastic, and viscoelastic. However,
under the influence of an applied pressure, the particles not only deform plasti-
cally or elastically, but also fragment to form smaller particles. The latter is
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
COMPRESSION PHYSICS IN THE FORMULATION DEVELOPMENT
termed as brittle fracture. The type of deformation depends not only on the
physical properties of the material but also on the rate and magnitude of the
applied force and the duration of locally induced stress.30
As a result of the resistance of a material against deformation (strain), the
stress inside the particles increases. If the applied stress is released before the
deformation reaches a specific critical value, the particles deform elastically, i.e.,
the deformation is reversible and the particles inside the powder bed regain
their original shapes. Until this critical value, the stress is linearly proportional
to the deformation and is characterized by elastic or Young’s modulus (E)36
(Figure 3a). For the brittle materials, particles fragment into smaller units at a
certain stress value (σf). This stress is the fracture strength (Figure 3b). For duc-
tile/plastic materials, after a critical stress (σy), the particles yield and start to de-
form plastically. This critical stress is the yield strength of a material (Figure 3c).
Material fracture eventually occurs at higher deformations. Elastic deformation
is a reversible process, whereas plastic deformation results in a permanent
change in the particle shape. The deformation mechanism for a few representa-
tive pharmaceuticals is presented in Table 1.
σf Fracture
Strength
σy
Fracture
Yield Strength
Strength c2
Stress
c1
E E E
a b c
Strain
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
S. PATEL, A.M. KAUSHAL, & A.K. BANSAL
10
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
COMPRESSION PHYSICS IN THE FORMULATION DEVELOPMENT
formulation can produce a good tablet on a slow machine speed, but fails on a
higher machine speed.48
However, dominating bond types for dry powders are solid bridges, mechanical
interlocking and intermolecular forces. Intermolecular forces include Van der
Wall’s forces, hydrogen bonding, and electrostatic forces. These bonds are of a
special importance for directly compressible binders such as microcrystalline
cellulose (MCC), polyvinyl pyrrolidone (PVP), and lactose.
The strength of a given plane within a tablet is described by the sum of all
11
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
S. PATEL, A.M. KAUSHAL, & A.K. BANSAL
attractive forces between the particles in that plane. It is assumed that all inter-
particulate bonds in the failure plane break more or less simultaneously.9 The
application of fracture mechanics has also been studied in relation to the me-
chanical strength of pharmaceutical tablets.51 The fracture mechanics concept
stresses the importance of defects and flaws in the tablet, which can be consid-
ered as starting points for the fracture, and the subsequent propagation of the
fracture. The propagation of fracture is considered to be a kinematic process.52
A fracture may be regarded as either brittle or ductile. A brittle fracture gener-
ally propagates rapidly, whereas a ductile fracture is characterized as being pre-
ceded by plastic deformation.
12
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
COMPRESSION PHYSICS IN THE FORMULATION DEVELOPMENT
tablet and the distribution of pores and particles within it. A number of tablet
properties are directly or indirectly related to the relative density of a tablet and
changes in tablet properties, such as mechanical strength, is related to percola-
tion thresholds.59 At a percolation threshold, one of the component percolates
throughout the system and properties of tablets are expected to experience a
sudden change. It is assumed that a tablet can only be produced with a certain
minimal amount of a well compactable substance which is needed to build a
percolating cluster in the tablet.
Besides the percolation threshold of the relative density, a threshold of the
mass fraction also exists. An interpretation can therefore be provided for the di-
lution capacity of a direct tableting excipient with a poorly compactable drug. A
direct tableting excipient has the ability to incorporate a certain amount of a
poorly compactable drug. The dilution capacity is understood as a critical value
of the mass fraction above which the compactibility of the tableting mixture
vanishes. The problem of finding the dilution capacity seems to be related to
the problem of elucidating a percolation threshold of the excipient. Theoretical
tools can also be applied to mixtures of more than two substances9 if they con-
sist of a single well compactable excipient and several poorly compactable
components. Such mixtures are relevant for the development of directly com-
pressible tableting formulations.60
IV.A. Precompression
Precompression is the stage where the tablets are partially formed and the pre-
compression roller is usually smaller than the compression roller, so that the
applied force is smaller in precompression stage. Optimal compression effi-
ciency is achieved on a machine that offers multistage compression with high
precompression and a desirable main compression force. Precompression plays a
major role especially at high compression speeds.40 For products that undergo
brittle fracture, the application of precompression at a higher force than main
compression results in higher tablet hardness. However, this is not the case for
material with elastic property, because this product requires gradual application
13
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
S. PATEL, A.M. KAUSHAL, & A.K. BANSAL
of force to minimize elastic recovery and allow stress relaxation. Similar sizes
for main and precompression rollers to apply similar forces are reported to re-
sult in optimal tablet formation.6
IV.C. Decompression
As the applied force is removed, a new set of stresses within the tablet gets
generated as a result of elastic recovery. The tablet must be mechanically strong
enough to accommodate these stress, otherwise the structure failures occur.
The degree and rate of relaxation within the tablet is the characteristic of a par-
ticular blend. Recording of this phase provides insights into tableting problems.
For example, if the degree and rate of elastic recovery are high, the tablet may
cap or laminate. If the tablet undergoes brittle fracture during decompression,
the compact may form failure planes as a result of fracturing of surfaces. Tab-
lets that do not cap or laminate are able to relieve the stresses by plastic defor-
mation. Since the plastic deformation is time dependant,47 stress relaxation is
also time dependant. The tablet failure is affected by rate of decompression (ma-
chine speed).62 Addition of a plastically deforming agent (e.g., PVP, MCC) is ad-
visable to reduce the risk of such structure failures.6
IV.D. Ejection
The last stage in compression cycle is ejection from die. Ejection phase also re-
quires force to break the adhesion between die wall and compact surface and
other forces needed to complete ejection of tablet.6 Radial die wall forces and
die wall friction also affect the ease with which the compressed tablet can be
removed from the die. The force necessary to eject a tablet involves the distinc-
tive peak force required to initiate ejection, by breaking of die wall–tablet adhe-
14
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
COMPRESSION PHYSICS IN THE FORMULATION DEVELOPMENT
sion. The second stage involves the force required to push the tablet up the die
wall, and the last force is required for ejection. Variation in this process are
sometimes found when lubrication is inadequate and a slip-stick condition oc-
curs between the tablets and die wall, with continuing formation and breakage
of tablet die–wall adhesion.6 Heat is generated during ejection as a result of fric-
tion from shear between the compact and the die wall, and absorption of this
heat can aid in bond formation. The shear forces during ejection can produce
additional plastic flow and afford consolidation not achieved during the com-
paction event. Lubrication usually assists in reducing the ejection forces, how-
ever it also has the negative effect on compact strength because of reduction in
cohesion characteristics.26 The unequal stress exerted on the compact during
ejection can cause stress planes that break bonds and result in compact capping
or laminating.63 Lubricants minimize stress patterns so, they reduce the ten-
dency for materials to cap or laminate.64 The particle size of the powdered ma-
terial also has an effect on ejection forces and shear. As particle size decreases,
more of its surface may be in contact with the die wall.65 This adds to increased
friction forces and the generation of heat. If more particle surface is available for
contact with the die wall, larger forces may be required to remove the compact.
V. INSTRUMENTATION
The production of compressed tablets is a complex process involving many
variables and a number of engineering principles. Fundamental research con-
cerning tablet manufacture has been ongoing for a number of years. Use of in-
strumented tablet machine is essential for basic research in compression physics,
as it facilitates product development, optimization and scale up, and enables
monitoring and control of production, by providing significant information
about the compression and ejection forces involved in the tableting operation.
Accurate measurement of these forces enables scientific designing of a tablet
formulation with desired attributes. Research and product developmental work
can be carried out to establish general relationships between the force of com-
pression and the physical properties of tablets such as thickness, hardness, fri-
ability, density, disintegration, and dissolution times. The resulting data can be
used to screen, and compare tableting excipients and their levels in formula-
tions and also aid in developing in-process quality controls. The instrumenta-
tion available include those that are inbuilt or fixed in the compression machine,
attachable ones such as instrumented punch die sets, and compaction simula-
tors that mimic the tableting cycle.
15
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
S. PATEL, A.M. KAUSHAL, & A.K. BANSAL
characteristics of high speed tableting machines. These are inserted into punch
guides, and a radio telemetry system is used to extract the force and displace-
ment signals. The strain gauges are mounted as closely as possible to the tips of
the punches to minimize errors resulting from longitudinal punch distortion
during compression. The displacement transducer is mounted in a punch guide
adjacent to a standard punch that is modified to couple it mechanically to a
transducer. A battery powered transmitter rotating with the turret, and com-
bined with an aerial bonded to the circumference of the turret, sends the signals
to a receiver mounted on a tie bar of the machine.66 The data is then accumu-
lated or transmitted via telemetry to a computer. Several instrumented punches
having strain gauges and other built-in instrumentation such as Portable Press
Analyzer™ (Puuman Oy, Finland), Director™ (SMI Inc., New Jersey, USA),
Presster™ (Metropolitan Computing Corporation, New Jersey, USA) are avail-
able commercially. Such devices are versatile enough to report compression
force and punch displacement or acceleration. The instrumented punches are
limited to one size and shape of tooling, and limited to one station, compared
to the roll-pin instrument that reports data for all stations and any tooling.
Presster™ is a versatile instrument designed to mimic a punch force-displace-
ment profile and gives choice of interchangeable precompression/compression
rolls and can fit different sizes and shapes of tooling to mimic the loading pattern
of any tablet press. SMI punches report measurements in terms of punch accel-
eration, but that can not be integrated to produce a true punch displacement sig-
nal because the integration constants (zero point velocity) are not known. At-
tempts to calculate displacement from acceleration have not yet been validated.
16
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
COMPRESSION PHYSICS IN THE FORMULATION DEVELOPMENT
force output is independent of the contact position of the punch. This can be
achieved by inserting strain gauges in a metal platform that is then mounted
below a modified ejection cam.20 Instrumentation is also available to measure
sweep-off force to predict the force of adhesion between a tablet and the
lower punch.6
Die-wall instrumentation is another type of instrumentation that gives in-
formation about transmitted radial stress that can be used to assess lubricating
properties of materials.67 It is also useful for elucidating the friction phenomena
during compaction and related tableting problems such as capping, lamination
and tooling wear. In fact, capping and lamination often originate in the com-
pression and decompression phases, but become evident at ejection phase.68
17
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
S. PATEL, A.M. KAUSHAL, & A.K. BANSAL
1. Force-Time Profile
Compression force-time profiles are used to characterize compression behavior
of active ingredients, excipients, and formulations with respect to their plastic
and elastic deformation.38 Various attempts have been made to characterize
compression force-time profiles from single punch and rotary tablet press. On a
rotary tablet press, the force-time curves are segmented into three phases—
compression phase, dwell phase, and decompression phase (Figure 4).69 The
force-time profile gives information about these phases as well as various char-
acteristic parameters of the compression cycle. Consolidation time is the time to
reach maximum force, dwell time is the time at which maximum displacement
occurs, and contact time is the time for compression and decompression.70 Pa
a b
Compression Force (kN)
a b c
Time (ms)
18
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
COMPRESSION PHYSICS IN THE FORMULATION DEVELOPMENT
rameters such as compression area (A1) and the compression slope (Slc) describe the
initial phase;38 the area ratio (AR),71 and the peak offset time (toff) characterize the
dwell time;72 and the decompression area (A4) and the decompression slope (Sld) de-
scribe the terminal phase. On a rotary tablet press, dwell time exists because the
punches do not move actively in vertical position when they are with their plane
punch-head area under compression roller38 (Figure 4). The total area under the
force-time curve (Atot),70 AR, toff, Slc, and A1 are used for phase-specific alloca-
tion of the occurrence of plastic flow, which is found to be a function of com-
pression force12 and moisture content.39 Tablet strength,73 tablet porosity, and
in-die bulk porosity23 provide additional information for comprehensive inter-
pretation.
In Figure 5 the compression force-time curve is shown divided into com-
pression, dwell-time, and decompression phases. The area under the curve A1
represents compression phase. For a constant tablet weight, A1 is small for
powder having high density, (e.g., dicalcium phosphate dihydrate (DCP)) and
large for those having low density (e.g., MCC). Areas A5 and A6 are obtained by
drawing a parallel line to x-axis from starting to the end point of dwell phase.
Plastic materials show a decrease in force over dwell time, in contrast a plateau
is observed for brittle materials (DCP, crystalline lactose), and therefore the
A5 A6
Compression Force (kN)
A1 A2 A3 A4
Time (ms)
FI GURE 5 . Com pression force- t im e curve for m icrocryst alline cellulose
( Avicel ® PH102) showing, t he com pression phase ( A1 ) , t he dwell t im e
phase ( A2 + A3 ) , and decom pression phase ( A4 ) . Areas A5 and A6 are ob-
t ained by drawing a parallel line t o X- axis from st art ing t o t he end point
of dwell phase, and t he rat io ( A6 / A5 ) can be used t o m easure t he plast ic-
it y of a subst ance. ( Adapt ed from Ref. 38 wit h perm ission from Elsevier.)
19
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
S. PATEL, A.M. KAUSHAL, & A.K. BANSAL
Stress relaxation
at constant strain
Pressure (MPa)
Displacement (mm)
toff
Time (ms)
20
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
COMPRESSION PHYSICS IN THE FORMULATION DEVELOPMENT
for brittle materials, stress relief does not depend on the rate of application of
stress.72 The difference between times, (tdiff) of maximum forces and the respec-
tive maximum densifications, and the occurrence of the maximum force before
the maximum of volume reduction can only be attributed to relaxation by plas-
tic flow (Figure 7). The area under the compression curve, AI, includes the in-
crease in force caused by densification and the decrease in force at reducing
rates of densification by relaxation. This area represents the compression phase
and the first half of the dwell time. The area under the decompression curve,
AII, is a measure predominantly of fast elastic expansion. Both the differences
in time and in displacement have been proposed to be measures of relaxation.70
2. Force-Displacement Profile
Stress relaxation is observed to be minimal in case of plastic deformation;
where as materials that undergoes elastic deformation tend to relax to a greater
extent during and/or after decompression. However, it has been observed that
t diff
F max S min
Force (kN)
Displacement (mm)
AI A II
Time (ms)
21
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
S. PATEL, A.M. KAUSHAL, & A.K. BANSAL
most of the materials undergo both plastic and elastic deformation at different
stages of compression, hence the work required for compression is the sum of
work necessary to rearrange the particles, deform, and finally to fragment
them.48
A common method for assessment of the compaction behavior of materials
is the use of compression force versus punch displacement profiles,71 from
which the work involved during tablet compaction can be calculated75 (Figure
8). Force-displacement profiles can be used for the determination of plastic and
elastic behavior.75 In a typical instrumented tablet machine, net work of compaction
(NWC) is calculated by subtracting the work of elastic relaxation (WER) from the
gross work of compaction (GWC). So NWC includes work against frictional forces
and work required for deformation and/or fragmentation.76,77
NWC = GWC – WER (3)
GWC = Wf + Wp + We + Wfr (4)
where, Wf is work against friction, Wp is work of plastic deformation, We is work of elastic
deformation, Wfr is work of fragmentation, with We ≈ WER.
This information can be used to predict the compaction behavior of phar-
maceutical materials as well as to explain the behavior of the material during
compaction. However, to be able to characterize the inherent deformation
properties of a material by force-displacement measurements, tableting should
not be affected by particle interaction during compaction, i.e., friction and
Force (kN)
Plastic Deformation +
Frictional Work
Elastic
Deformation
Displacement (mm)
FI GURE 8 . Force- displacem ent profile showing t he plast ic deform at ion
and frict ional work, and t he elast ic deform at ion areas.
22
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
COMPRESSION PHYSICS IN THE FORMULATION DEVELOPMENT
23
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
S. PATEL, A.M. KAUSHAL, & A.K. BANSAL
friction coefficient (µ2), which gives the force to maintain sliding between two
surfaces.83
Time (ms)
Tableting
Process
FI GURE 9 . Force and punch displacem ent s profiles during t ablet ing
process. ( Adapt ed from Ref. 80 wit h perm ission from Elsevier.)
24
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
COMPRESSION PHYSICS IN THE FORMULATION DEVELOPMENT
wall force reaches a maximum just after the maximum upper and lower force,
and a constant residual value after upper and lower forces became zero, until
the ejection process starts, when it again increases.80 The residual die wall force
is the average of values in the constant region at zero upper punch force, with
the difference of displacement between upper and lower punch, giving a meas-
ure of the tablet area contact with the die wall. Residual die wall force depends
on deformation behavior of particles under force. For materials that undergo
plastic deformation,86,87 a large residual die wall force is observed, in contrast to
lower force for elastic materials as a result of their large relaxation behavior.
Brittle materials show medium values of the residual die wall force as a result of
considerable fragmentation and a large peak at ejection. The high die wall force
during ejection is a sign of adhesion of powders to the die, and a reduction of
this die wall force is effective in improving the tableting process.80
1. Kawakita Equation
The basis for the Kawakita equation for powder compression is that the parti-
cles are subjected to compressive load in equilibrium at all stages of compres-
sion, so that the product of pressure term and volume term is constant.88 The
Kawakita equation is
where, Pa is the applied axial pressure, a is the degree of volume reduction for
the bed of particles, and b is a constant proposed to be inversely related to the
yield strength of particles. C is the degree of volume reduction, V is volume of
compact at pressure, and V0 is the initial apparent volume of powder.89 This
equation holds best for soft fluffy pharmaceutical powders, and is best used for
low pressures and high porosity situations.24
25
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
S. PATEL, A.M. KAUSHAL, & A.K. BANSAL
2. Heckel Equation
The Heckel model90,91 provides a method for transforming a parametric view of
the force and displacement signals to a linear relationship for purely plastic ma-
terials. This makes the Heckel model a convenient method for interpretation
and the most frequently used relationship between relative density and applied
pressure.92 The Heckel equation is based on the assumption that densification
of the bulk powder under force follows first-order kinetics (Figure 10).
The Heckel equation is expressed as
ln [1/1–D] = KP + A (9)
Slope = K
A Da
B D0
FI GURE 1 0 . A t ypical Heckel plot derived from relat ive densit y and
com pact ion pressure. Region I corresponds t o part icle rearrangem ent at
low pressure, whereas region I I , t he linear part of t he curve shows t he
abilit y of t he m at erial t o deform plast ically. At higher pressures, region
I I I is observed due t o work hardening. D a gives densificat ion due t o ini-
t ial part icle rearrangem ent , whereas D 0 gives densificat ion due t o init ial
die filling. ( Adapt ed from Ref. 13 wit h perm ission from Elsevier.)
26
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
COMPRESSION PHYSICS IN THE FORMULATION DEVELOPMENT
where, D is the relative density of the tablet (the ratio of tablet density to true
density of powder) at applied pressure P, and K is the slope of straight line por-
tion of the Heckel plot. Reciprocal transformation of the slope gives
mean yield pressure, Py. In-die measurements of the tablet thickness give appar-
ent mean yield pressure, and the intercept of linear portion A gives densifica-
tion of the powder as a result of initial particle rearrangement (Da)
A = ln [1/1–D0] + B (10)
Da = 1 – e-A (11)
where, ln [1/1–D0] is related to the initial die filling and B is the densification as
a result of slippage and rearrangement of primary and fragmented particles (DB). B
From the point B where the Heckel Plot intercepts the Y-axis, D0 is ob-
tained (zero pressure powder density), which is defined as the densification as a
result of die filling or initial powder packing.
D0 = 1 – e-B (12)
DB = DA – D0 (13)
In 1961, Heckel proposed a relationship between the constant K and the yield
strength for a range of metal powders.
K = 1/3 σ (14)
where, σ is the yield strength of the material. K is inversely related to the ability
of the material to deform plastically. Heckel studied mainly metal powders and
the equation was only meant for materials that compact by plastic deformation.
The term 3σ (=1/K) is often called the yield pressure. Heckel parameters have
been shown to be more dependent on the compression–decompression cycle
than on the size of die.93
Methods used to collect data for Heckel transformation are in-die or at-
pressure and out-of-die or zero pressure after ejection of the compact. In the in-die
method,94,95 results can be influenced by an elastic deformation under pressure,
which lowers the porosity. Therefore the out-of-die or zero-pressure measurement
describes powder behavior more accurately,96 and hence is a reliable method for
obtaining yield strength and avoiding contribution of elastic deformation. How-
ever, the in-die method is still commonly used to derive the yield strength of
powders because it requires less time and effort. Although important, a quanti-
tative comparison between these two methods is not available.
Three regions for an in-die Heckel plot may be observed97,98 (Figure 10).
The first region corresponds to low-pressure, where the curvature arises from
particle rearrangement before a plastic deformation takes place. The second re-
gion is the linear part of the plot in the medium pressure range representing
material’s ability to deform plastically under pressure. At the high-pressure re-
gion, the curvature has been attributed to work (strain) hardening97,99 and to a
27
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
S. PATEL, A.M. KAUSHAL, & A.K. BANSAL
change in crystal density. However, Sun and Grant explained the curve behav-
ior in the last region with an elastic deformation of the powder. This elastic de-
formation can even lead to a negative porosity and a value for relative density
higher than one.100
Roberts and Rowe74 proposed an additional study on the effect of punch
velocity to understand the compression process. Strain rate sensitivity (SRS)
was measured according to equation
SRS = [Py2 - Py1/Py2] 100 (15)
where, Py1 is the yield pressure at low speed and Py2 is the yield pressure at high
speed.101 Although Heckel only applied pressures between 69 and 690 MPa, he
postulated that extrapolation of the values to even higher pressures are justified,
because linearity exists over nearly 80% of the pressure range.97 Relative density
is always influenced by determination of true density, tablet weight, and tablet
volume. Therefore, data points at relative density more than 0.95 should be
used with caution, because they can cause deviations from linearity.96 Kuentz
and Leuenberger102 postulated a modified Heckel equation which allows the de-
scription of the transition between the states of a powder to the state of a tablet.
1⎡ ⎛ 1− ρ ⎞⎤
σ= ⎢ ρ c − ρ − (1 − ρ c ) ln⎜⎜ ⎟⎟⎥
C⎣ ⎝1 − ρc ⎠⎦ (16)
where, σ is the pressure, ρ is the relative density, ρc is the critical density, and C
is a constant. Similar to the constant K in the Heckel equation, the constant C
in the modified Heckel equation shows high values for plastic behavior and low
values for brittle powder behavior.
Although Heckel plots are mostly used to characterize single materials, they
can also be used for powder mixtures. Ilkka and Paronen92 investigated binary
mixtures and reported that all the mixtures behaved like intermediate materials
between the bulk mixture components. Yet, no exact linear relationship in be-
havior between the mixtures and bulk components was seen. In most of the
cases, one mixture component seemed to have more effect on the densification
of the powder mixtures than the other.
3. Walker Equation
The Walker equation103 is based on the assumption that the rate of change of
pressure with respect to volume is proportional to the pressure, thus giving a
differential equation
Log P = –L x V′ / V0 + C1 (17)
28
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
COMPRESSION PHYSICS IN THE FORMULATION DEVELOPMENT
The evaluation of drug substances and pharmaceutical excipients for their phys-
ico-mechanical properties is of prime importance in the development of
oral solid dosage forms. Apart from tensile strength and porosity–pressure rela-
Heckel
Walker
ln[1/(1-D)]
10-(1/D)
Relative Density
29
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
S. PATEL, A.M. KAUSHAL, & A.K. BANSAL
30
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
COMPRESSION PHYSICS IN THE FORMULATION DEVELOPMENT
31
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
S. PATEL, A.M. KAUSHAL, & A.K. BANSAL
32
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
COMPRESSION PHYSICS IN THE FORMULATION DEVELOPMENT
needed to enhance the compressibility of starches and facilitate their plastic de-
formation.137 Hence, moisture can increase plastic deformation and reduce elas-
tic property of powder material and reduce the ejection force. Shotton and Rees
reported an increased sodium chloride punch force ratio (R) at 0.55% moisture
for low applied force. This effect was explained by reduced friction caused by
the formation of moisture film acting as a die wall lubricant. Lower moisture
contents provided less die-wall lubrication at all values of applied force.134
33
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
S. PATEL, A.M. KAUSHAL, & A.K. BANSAL
34
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
COMPRESSION PHYSICS IN THE FORMULATION DEVELOPMENT
1. Hydration/Solvate State
The need for optimal moisture content in the formation of strong tablets is in-
dicated by crystal hydrates that compress well, but fail to form strong tablets
35
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
S. PATEL, A.M. KAUSHAL, & A.K. BANSAL
2. Crystal Habit
Isomorphic forms of drugs differ only in their crystal habit. Tableting behavior,
flowability, and the tendency to stick to the punches can be affected by the
crystal habit of the drug(s). Crystal engineering and particle design can be effec-
tively used to improve compactibility.10 In a study by Sun et al. on the influence
of crystal shape on the tableting performance, prism and plate shaped crystals
of L-lysine monohydrochloride dihydrate, were evaluated. Greater tabletability
of plates when compared to prisms was a result of its better compactibility that
overcame the negative effects by its lower compressibility. This was a result of
favorable orientation of the slip planes in the plates, corresponding to greater
plasticity under load.11 In a study, polyhedral and thin plate-like crystal habit of
paracetamol influenced the compression property, which was also investigated
by the Heckel plots and their associated parameters. The correlation coefficient
of the initial part of the Heckel plots, and also the values of SRS, were lower for
thin plate-like crystals, indicative of greater fragmentation as compared to poly-
hedral crystals. Compacts made from thin plate-like crystals exhibited higher
elastic recoveries as a result of lesser plastic deformation during compression
than for polyhedral crystals.13 Production of sintered-like crystals of paraceta-
36
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
COMPRESSION PHYSICS IN THE FORMULATION DEVELOPMENT
mol for direct compression was prepared by recrystallization from a dioxane so-
lution or suspension.151
Phenytoin crystals having varied habits were prepared by recrystallization
from ethanol and acetone solutions under different conditions. The compacts
of phenytoin crystals produced from alcohol or acetone had higher crushing
strengths than untreated phenytoin as a result of the lower porosity and the
lower elastic recovery.152 The compaction characteristics of a new drug sub-
stance with two crystal habits and particle size fractions as well as its binary
mixtures with MCC were studied. The three-dimensional hexagonal crystal
habit or smaller particle size gave a slightly higher total work of compaction as
compared to cubic brick habit or larger particle size, respectively.153
3. Polymorphism/Amorphism
Differences in the physical and chemical properties of various drug substance
polymorphic forms are well documented. In a study on compression behavior
of pure orthorhombic or monoclinic paracetamol, orthorhombic crystals exhib-
ited better technological properties due to presence of sliding planes for crystal
plasticity, greater fragmentation at low pressure, increased plastic deformation
at higher pressure, and lower elastic recovery, thus avoiding capping even at
high compression pressures.7 In another study that related the effect of poly-
morphic structure of sulfamerazine on the tableting properties, form I showed
highest tensile strength, where as form II(B) showed minimum values and the
porosity at the same compaction pressure followed the order, I << II (A) < II
(B). Greater plasticity and compressibility was attributed to the slip planes pre-
sent in form I crystals.154 Acetaminophen is known to exist in two polymorphic
forms. The thermodynamically stable form I (monoclinic) gave unstable tablets
with high capping tendency as a result of a stiff construction of the molecules
inside the crystal, whereas, form II (orthorhombic) showed better compression
behavior as a result of presence of sliding planes.155
The complete absence of long-range, three-dimensional, intermolecular or-
der associated with amorphous materials might significantly modify the me-
chanical properties of a powdered amorphous drug substance.124 Amorphous
α-cyclodextrin,156 spray-dried lactose,157 showed improved in compaction be-
havior. The improvement in compaction behavior of amorphous materials can
be attributed to higher plastic deformation than their crystalline counterparts.
37
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
S. PATEL, A.M. KAUSHAL, & A.K. BANSAL
and tablet tensile strength are important to select and design appropriately sized
particles. Two particle size fractions (<90 micron and 105–210 micron) of
paracetamol were examined for their compaction properties. Each fraction
produced extremely weak tablets with capping. The 105–210 micron particles
underwent more fragmentation than 90 micron particles. Heckel analysis con-
firmed that the larger size fraction of paracetamol produced denser compacts
than the smaller fraction with lower elastic recoveries and elastic energies.12
Fichtner reported that the spread in particle size of paracetamol had no in-
fluence on the evolution in tablet porosity and tensile strength during compres-
sion, but had a significant and complex influence on the short-term post-
compaction hardening. It was concluded that the distribution in size of free-
flowing particles is not critical for the tablet porosity, but may give significant
effects on tablet tensile strength as a result of postcompaction hardening.158 A
study related to the effect of particle size of L-lysine monohydrochloride di-
hydrate on compaction showed that compression of smaller particles at low
compaction pressures resulted in tablets of greater porosity. At the same com-
paction pressure, tensile strength of tablets increased with decreasing particle
size as a result of a larger number of contact points between smaller crystals
and more homogeneous distribution of pores. Increasing yield strength with in-
creasing particle size indicates greater apparent plasticity of the smaller particles.
However, fragmentation of the larger particles tended to equalize the particle
size and reduce its influence.34
Particle agglomeration behavior of a novel drug substance DPC 963 was af-
fected by particle size, with smaller particle size giving higher pore volumes,
suggesting lower densification tendency as compared to the larger drug particle
size. Granule compressibility was increased by decreased in drug particle size.
The effect of particle size on granulation growth was a result of increased den-
sification propensity, as a result of increased drug substance particle size.159 A
recent paper by Sun et al. discussed about the reduced tabletability of roller
compacted MCC as a result of granule size enlargement. This was attributed to
lower surface area in larger granules, thus leading to lower tensile strength as
compared to smaller granules.8
38
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
COMPRESSION PHYSICS IN THE FORMULATION DEVELOPMENT
39
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
S. PATEL, A.M. KAUSHAL, & A.K. BANSAL
40
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
COMPRESSION PHYSICS IN THE FORMULATION DEVELOPMENT
non,47 therefore stress relaxation depends on dwell time and rate of force trans-
fer to the powder bed,14 with rapid compression and decompression more likely
to result in tablet failure. Tablet capping or lamination problems are also associ-
ated with pre- and main compaction profile.12 Measures such as, applying pre-
compression, slowing tableting speed (longer dwell time), and reducing final
compression force may help mitigate capping/lamination.168
The type of tooling used can also have an effect on capping or lamina-
tion.169,170 Often deep concave punches give capping as a result of more radial
expansion and shear stress in cap region than in body of the tablet. Flat
punches produce less shear stress within compact.171 Dies also develop a wear
ring in the areas of compression and the tablets compressed in the ring have
fewer diameters to pass through die wall, resulting in capping and/or lamina-
tion upon ejection. Incorrect set up of tableting press is another cause of cap-
ping/lamination and proper adjustment of lower punch and sweep off plate is
essential. Moisture plays a key role in bonding mechanism and plastic deforma-
tion,39,172,173 and therefore, granules or powder having less moisture tends to cap
or laminate. Addition of hygroscopic substances such as methyl cellulose, sorbi-
tol, and PVP can help to maintain proper moisture level in such cases.4
Picking is a term used to describe the removal of surface material of tablet
by a punch. Picking is often a concern with punch having engraving or emboss-
ing. Some letters such as “A,” “B,” and “O” are difficult to manufacture cleanly.
To reduce this problem, lettering should be as large as possible or tablet can be
formulated in larger size.4 Sticking refers to tablet material adhesion to die wall.
Punch surface roughness,169 compaction force and the blend composition are
significant factors contributing to sticking. Chrome plating of punch faces in-
creases sticking at a low compaction force but decreases it at higher forces.170
Low melting substance either active ingredient (e.g., ibuprofen) or additive
(stearic acid and PEG) may soften as a result of heat generation during com-
pression. Addition of high melting additives in the formulation, refrigeration of
granules, and cooling of tableting press can be used. Monitoring the moisture
level is also important for controlling these problems, as increased moisture has
been related to sticking and picking.
41
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
S. PATEL, A.M. KAUSHAL, & A.K. BANSAL
diluents, and binders are critical to minimize tableting problems. The selection
and/or modification of blend components is dictated by their compression be-
havior, when present alone or in combination. An example of this approach is
the choice of blend/coprocessing components based on their complimentary
nature (plastic versus brittle).
1. Diluents
Diluents play the most critical part among all the excipients, because they are
usually present in amounts greater, than other excipients. Diluents range from
highly compressible materials such as MCC, to those with very low compressi-
bility such as starch. As described previously, the main behavioral patterns of
pharmaceuticals under compaction are plastic deformation, elastic deformation,
and brittle fracture. Material having plastic deformation properties such as
MCC51 and amorphous binders exhibit higher number of attractive forces,
which contribute to higher compact strength. Rough surface on the particles
42
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
COMPRESSION PHYSICS IN THE FORMULATION DEVELOPMENT
monly used tableting diluents and their compaction properties are given in Ta-
ble 4.
Over the years, there has been a perceptible shift towards direct compression
for manufacture of tablets. The term direct compression is used to define the process
by which tablets are compressed directly from the powder blends of active ingredi-
ent(s) and suitable excipient(s). Direct compression is a simple and economical
process in terms of fewer unit operations and fewer stability issues for heat or
moisture sensitive compounds. However, not all pharmaceuticals are amenable to
direct compression and it is estimated that only about 20% of pharmaceutical ma-
terials can be compressed directly into tablets.181
Although direct compression is a simpler process, it demands increased per-
formance from the excipients, especially diluents. Ideal requirements of a di-
rectly compressible diluent include good compressibility, free flow, and low
segregation tendency.3,133 The suitability of a diluent for direct compression can
be quantified in terms of its dilution potential, which is defined as the amount
of an active ingredient that can be satisfactorily compressed into tablets with a
directly compressible excipient. The dilution potential is generally expressed in
terms of percentage of noncompressible material or as optimum drug to diluent
ratio. Higher dilution potential can help in incorporation of high amount of
poorly compressible drug(s)182 and small tablet size. However, the dilution po-
tential of a diluent is also influenced by how poor is the compressibility of
drug(s). Also, directly compressible adjuvant should be capable of being re-
worked without loss of compressibility or flow.
Excipients, per se might not be amenable to direct compression, however,
their properties can be modified by granulation, agglomeration, and coprocess-
ing. Coprocessing has emerged as a popular way to generate directly compressi-
ble excipients. In the absence of a chemical change during processing, coproc-
essed excipients can be considered generally regarded as safe (GRAS) if the
parent excipients are also GRAS-certified.183 This ensures rapid commercializa-
tion without the need for rigorous safety testing.184 Coprocessing is defined as
43
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
S. PATEL, A.M. KAUSHAL, & A.K. BANSAL
44
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
COMPRESSION PHYSICS IN THE FORMULATION DEVELOPMENT
2. Lubricants
As with other classes of pharmaceutical excipients, lubricating agents are added
to the formulation of solid dosage forms to aid in the manufacture and ensure
appropriate quality of the finished products. Lubricant is best identified as a
suitable material, a small amount of which, when interposed between two rub-
bing surfaces, will reduce friction arising at the interface. According to the basic
mechanism by which they act, lubricants are divided mainly into two types201 (i)
hydrodynamic or fluid lubricants, and (ii) boundary lubricants. The hydrody-
namic or fluid lubricants act by completely separating the moving surfaces by
forming a layer. Resistance to motion arises solely by the viscosity of the lubri-
cant. Hydrodynamic lubrication is not a surface phenomenon and friction coef-
ficient values lie around 0.001 and thus doesn’t cause much wear of the tooling
(e.g., mineral oil).202 In boundary lubrication, die wall and the granular surfaces
are separated by lubricant layer penetrated by the surface asperities of granules,
which are the main cause for the production of friction. In contrast to the for-
mer, it is a surface phenomenon and friction coefficients are much higher
(0.05–0.15), and thus wearing of tooling does occur. However, good boundary
lubricants are tough enough in the form of films thus can resist and minimize
wear. They have low shear strength and hence readily form a film that is able to
reduce the contact area of granules with the die wall.
Commonly used lubricants include, water insoluble metallic stearates,
stearic acid, talc, and waxes; and water soluble materials such as boric acid, so-
dium benzoate, sodium acetate, sodium chloride, leucine, carbowax, sodium
45
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
MCC, Silicon dioxide Blending Prosolv™ (Penwest Pharmaceu- Better hardness of tablet, reduced friability better 210
ticals Company, USA) flow, reduced sensitivity to wet granulation
46
MCC, Guar gum Blending Avicel® CE-15 (FMC Corpora- Improved compaction with enhanced bonding 211
tion, USA) properties
Calcium carbonate (70%), Sor- Spray drying ForMaxx™ (Merck Chemicals Improved compaction and flow properties 212
bitol (30%) Ltd, UK)
α-Lactose monohydrate Spray drying Microcelac® (Meggle, Germany) Capable of formulating high dose small tablets 213
(75%), Cellulose (25%) with poorly flowable actives
-lactose anhydrous (95%), Milling Pharmatose® DCL40 (DMV High compressibility, low lubricant sensitivity 214
Lactitol (5%) Veghel, The Netherlands)
Lactose monohydrate (85%), Spray agglomeration StarLac™ (Roquette, France) Good compressibility and flow 215
native corn starch (15%)
Fructose (95%), Starch (5%) Spray drying Advantose™ FS 95 (SPI Polyols, Directly compressible powder 216
Inc. USA)
Maltose Spray drying Advantose™ 100 (SPI Polyols, Spray dried directly compressible maltose powder 217
Inc. USA)
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
TABLE 5. (Continued)
Calcium carbonate (90%), Spray drying Barcroft™ Cs 90 (SPI Polyols, Good compaction and flow behavior 218
starch (10%) Inc. USA)
Hydroxides of Al, Mg Spray drying Barcroft™ Premix St (SPI Direct compression antacid powder 219
and sorbitol Polyols, Inc. USA)
Xylitol, Sodium CMC Spray drying Xylitab® Danisco A/S, Den- Directly compressible xylitol 220
mark
Lactose, Sodium alginate Spray-drying — The tensile strength of composite particles is as high as spray- 221
dried amorphous lactose, with less elastic recovery than alpha-
lactose monohydrate
47
Rice starch, MCC Spray-drying — Compressibility of composite particles was greater than 222
commercial spray-dried Eratab®, Cellactose® and Tablettose®
MCC, Colloidal silicon Wet granulation — Good compressibility and flow 223
dioxide, Lactose
monohydrate, and DCP
Powdered cellulose, Mag- Roller compaction — Improved compaction than physical mixture 224
nesium carbonate
Lactose, PVP, polysor- Spray-drying — Compression behavior and tablet-forming ability of spray- 225
bate 80 dried amorphous lactose was modulated by the addition of
stabilizing polymers and surfactants
Key: MCC, microcrystalline cellulose; DCP, dibasic calcium phosphate; PVP, polyvinyl pyrolidone; Na-CMC, sodium cabroxy
methylcellulose
S. PATEL, A.M. KAUSHAL, & A.K. BANSAL
oleate, and sodium lauryl sulfate. Magnesium stearate (MS) is the most widely
used lubricant in tablet manufacturing because of its high lubrication potential.
However, MS has a negative effect on tablet tensile strength203 and dissolution
profile204,205 due to its hydrophobic nature which inhibits interparticulate bond-
ing by coating around drug particles.206 Colloidal silicon dioxide is often used as
a flow enhancer and it eliminates the negative effect of MS on interparticular
bonding while maintaining the lubrication action. This property of colloidal sili-
con dioxide is affected by its hydrophobicity/hydrophilicity and by the particle
deformation properties of the excipient upon compression.226 The choice of a
type and amount of lubricant is influenced by the deformation behavior of the
major component of the blend. Lubricated tablets show larger relaxation for
plastic materials, as a result of the reduction of interparticulate bonding by the
lubricant. While for brittle material, the lubricant film is destroyed by fragmen-
tation, minimally affecting the interparticulate bonding, hence only a small or
no effect on tablet relaxation is observed.203 Optimizations of lubricant concen-
tration in formulations are important to minimize problems related to dissolu-
tion and tensile strength. However, this has to be carefully balanced against the
requirement of MS to lubricate the blend, tooling and prevent tableting prob-
lems. Optimization is done by creating ejection profile of each lubricant to re-
duce the stresses related to tablet compaction. Also, various hydrophilic lubri-
cants are an alternative to eliminate dissolution and tablet hardness related
issues. Granular MS has been suggested as a viable alternative to ordinary MS,
as it does not affect the tensile strength, friability, disintegration, and dissolu-
tion.227 Lubrication properties were also compared among glycerin fatty acid es-
ters, MS and a sucrose fatty acid ester, and it was shown that lubricant charac-
teristics were similar to MS, and tablets were superior to those with MS in terms
of hardness, disintegration and stability.228 Compretol® (glyceryl dibehenate) as a
tablet lubricant showed similar performance at 0.5% concentration by hot melt
coating as compared to simple blending at 3% lubricant level.229
3. Disintegrants
Achievement of desired dissolution rate of drug substance(s) from a tablet re-
quires overcoming cohesive strength of tablet and breaking into primary parti-
cles. This is achieved by adding disintegrants into formulations. Commonly
used disintegrants, along with their usage concentration in parenthesis include
starch (3–15%), MCC (5–15%), pregelatinized starch (5–10%), croscarmellose
sodium (1–5%), sodium starch glycolate (2–8%), and crospovidone (2–5%).
The basic mechanism of disintegration is swelling in presence of water. The
ability of these materials to take up moisture from surroundings and conse-
quently swell can have a negative effect on tensile strength. Many of the com-
monly used diluents such as MCC and starch also possess disintegrant property.
48
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
COMPRESSION PHYSICS IN THE FORMULATION DEVELOPMENT
4. Granulating Agents/Binders
Granulating agents are used to form granules from powder. Water and organic
solvents act as a granulating agent by partially dissolving the surface of the par-
ticles and forming solid bridges upon evaporation. However, these types of
bonds are weak and lead to formation of friable granules. Therefore, it is usual
to include binder to granulations to increase granule strength and tackle the
problem of capping and lamination. Granulating agents are usually cohesive
hydrophilic polymers that aid in granulation process and impart strength after
drying.
Effective granulating agents form a film around particle surface. Rowe has
suggested that binder should be selected on the basis of their spreading coeffi-
cients, which is the difference between ‘work of adhesion’ of binder-particle
and ‘work of cohesion’ of the binder. Correlations have been found between
the spreading coefficient of the binder and actual experimental measurements
of granule friability, tablet strength and tablet capping.231 Particle size, sur-
face/surface structure, and plasticity of binders are known to influence binding.
The ideal dry binder should have small particles, high plasticity, and a large sur-
face area.232
Granulations with a more homogeneous distribution of binder generally
produce tablets of a higher mechanical strength than with a peripheral localiza-
tion of binder. Therefore, high granule porosity with homogeneous intragranu-
lar binder distribution is advantageous for the compactibility of a granulation.188
The ability of the binder to fill the voids between the particles/granules is the
determining factor for increasing strength and also the amount of binder added
to the mixture affects the results.44 Fine-particle ethyl cellulose233 as a tablet
binder in direct compression and the utility of fine-particle hydroxypropyl cellu-
lose234 as a roller compaction binder was shown to increase the contact area, re-
sulting in greater bond formation, and reduced problem of capping in tablets
containing highly elastic materials.
The strength of tablets containing a less plastic binder is governed by the
inherent compactibility of the blend. The tablet porosity, bonding mechanisms
49
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
S. PATEL, A.M. KAUSHAL, & A.K. BANSAL
and volume reduction mechanisms of the compound are also influenced by the
binders. For example, the plasticity and particle size of the binder has most sig-
nificant effects on tablet strength when the tablet porosity is low, whereas, the
plasticity and the compactibility of the binder determines the strength of tablets
when the tablet is more porous.44,235 Binder toughness is the property of binder
that quantifies the ability of a material to resist the crack propagation under ap-
plied stress. In a study, hydroxypropyl cellulose was reported to be the toughest
binder and had a very high degree of plasticity, when compared to methyl cellu-
lose, PVP, and starch. PVP and starch showed very low strength and toughness
with nearly nil to very little plastic flow.236
The choice of a suitable binder for a tablet formulation requires extensive
knowledge of binder properties for enhancing the strength of the tablet and
also the interactions between the various constituents of a tablet. Addition of a
binder, which increases elasticity, can decrease tablet strength because of the
breakage of bonds as the compaction pressure is released.237 PEG is a ductile
plastically deformable material with a moderate mechanical strength and its me-
chanical properties were found to relate to the average molecular weight.144,238,239
In a study using deformable binders, which did not fragment to any signifi-
cant extent (e.g., PEG and amorphous lactose), the disintegration time was ex-
tended and was not substantially affected by the addition of a superdisintegrant.
However, if the tablet was sufficiently porous, the negative effect of the binders
was reduced. When less deformable binders which are likely to fragment were
used, the effect of the superdisintegrant was substantial, and rapidly disintegrat-
ing tablets of high tensile strength were obtained.240
X. SUMMARY
Compaction is an integral step for the manufacture of tablets, and it is pertinent
to understand the underlying physics of compaction. Complete understanding
of compaction physics still eludes us, many variables such as inherent deforma-
tion behavior of drugs/excipients, solid-state properties, and process parame-
ters are known to affect the final attributes of tablets. A due consideration to
the variables of compaction process, can aid a pharmaceutical scientist to de-
sign optimum formulation devoid of problems such as capping, lamination,
picking, and sticking. Availability of sophisticated tableting instrumentations has
catalyzed the understanding of process, and the generation of compaction pro-
files such as force-time profile, force-displacement profile, and pressure–
porosity relationships can help in deciphering the dynamics of the process. The
compactibility of the drugs, especially in case of high dose systems, is critical for
successful manufacturing of tablets. An appreciation of the contribution of ta-
bleting excipients to the compaction behavior of the tablet-matrix can enable
50
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
COMPRESSION PHYSICS IN THE FORMULATION DEVELOPMENT
ACKNOWLEDGEMENT
Aditya M. Kaushal would like to acknowledge CSIR, India for providing senior
research fellowship. The insightful comments and suggestions of the reviewer
are gratefully recognized.
REFERENCES
1. Jeffrey L, Czeisier, Karl PP. Diluents. In: James CB, James S, editors.
Encyclopedia of Pharmaceutical Technology. New York: Marcel Dekker; 1991.
2. Gohel MC, Jogani PD. Functionality testing of a multifunctional directly com-
pressible adjuvant containing lactose, polyvinylpyrrolidone, and croscarmellose
sodium. Pharm Technol. 2002;25:64–82.
3. Gohel MC, Jogani PD. A review of co-processed directly compressible excipi-
ents. J Pharm Pharm Sci. 2005;8:76–93.
4. Banker GS, Anderson NR. Tablets. In: Lachman L, Liberman HA, Kanig JL,
editors. The Theory and Practice of Industrial Pharmacy. 3rd ed. Bombay:
Varghese Publishing; 1976.
5. Guo HX. Compression behavior and enteric film coating properties of cellulose
esters [dissertation]. Finland: University of Helsinki; 2002.
6. Marshall K. Compression and consolidation of powdered solids. In: Lachman L,
Lieberman HA, Kanig JL, editors. The Theory and Practice of Industrial Phar-
macy. 3rd ed. Bombay: Varghese Publishing; 1987.
7. Joiris E, Di Martino P, Berneron C, Guyot-Hermann AM, Guyot JC. Compres-
sion behavior of orthorhombic paracetamol. Pharm Res. 1998;15:1122–30.
8. Sun C, Himmelspach, MW. Reduced tabletability of roller compacted granules as
a result of granule size enlargement. J Pharm Sci. 2006;95:200–6.
9. Leuenberger H, Leu R. Formation of a tablet: a site and bond percolation phe-
nomenon. J Pharm Sci. 1992;81:976–82.
10. York, P. Crystal engineering and particle design for the powder compaction
process. Drug Dev Ind Pharm. 1992;18:677–721.
11. Sun C, Grant DJ. Influence of crystal shape on the tableting performace of L-
lysine monohydrochloride dihydrate. J Pharm Sci. 2001;90:569–79.
12. Garekani HA, Ford JL, Rubinstein MH, Rajabi-Siahboomi AR. Effect of com-
pression force, compression speed, and particle size on the compression proper-
ties of paracetamol. Drug Dev Ind Pharm. 2001;27:935–42.
51
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
S. PATEL, A.M. KAUSHAL, & A.K. BANSAL
13. Garekani HA, Ford JL, Rubinstein MH, Rajabi-Siahnboomi AR. Formation and
compression characteristics of prismatic polyhedral and thin plate-like crystals of
paracetamol. Int J Pharm. 1999;187:77–89.
14. Akande OF, Ford JL, Rowe PH, Rubinstein MH. The effects of lag-time and
dwell-time on the compaction properties of 1:1 paracetamol/microcrystalline
cellulose tablets prepared by pre-compression and main compression. J Pharm
Pharmacol. 1998;50:19–28.
15. Pawar AP, Paradkar AR, Kadam SS, Mahadik KR. Crystallo-co-agglomeration: a
novel technique to obtain ibuprofen-paracetamol agglomerates. AAPS
PharmSciTech. 2004;5:e44.
16. Adam A, Schrimpl L, Schmidt PC. Factors influencing capping and cracking of
mefenamic acid tablets. Drug Dev Ind Pharm. 2000;26:489–97.
17. Di Martino P, Scoppa M, Joiris E, Palmieri GF, Andres C, Pourcelot Y, Martelli
S. The spray drying of acetazolamide as method to modify crystal properties and
to improve compression behavior. Int J Pharm. 2001;213:209–21.
18. Gohel MC, Jogani PD. Exploration of melt granulation technique for the devel-
opment of coprocessed directly compressible adjuvant containing lactose and
microcrystalline cellulose. Pharm Dev Technol. 2003;8:175–85.
19. Pontier C, Viana M, Champion E, Bernache-Assollant D, Chulia D. About the
use of stoichiometric hydroxyapatite in compression-incidence of manufacturing
process on compressibility. Eur J Pharm Biopharm. 2001;51:249–57.
20. Trevor MJ, Ho AYK, Barker MJ. The use of instrumentation in tablet research,
devlopment and production. Pharm Technol. 1985;42–8.
21. Booth SW, Newton JM. Experimental investigation of adhesion between pow-
ders and surfaces. J Pharm Pharmacol. 1987;39:679–84.
22. Otsuka A. Adhesive properties and related phenomena for powdered pharma-
ceuticals. Yakugaku Zasshi. 1998;118:127–42.
23. Sonnergaard JM. A critical evaluation of the Heckel equation. Int J Pharm.
1999;193:63–71.
24. Denny PJ. Compaction equations: a compression of the Heckel and Kawakita
equations. Powder Technol. 2002;127:162–72.
25. Jonat S, Hasenzahl S, Gray A, Schmidt PC. Mechanism of glidants: investigation
of the effect of different colloidal silicon dioxide types on powder flow by
atomic force and scanning electron microscopy. J Pharm Sci. 2004;93:2635–44.
26. Jarosz PJ, Parrott EL. Effect of lubricants on tensile strengths of tablets. Drug
Dev Ind Pharm. 1984;10:259–73.
27. Davies P. Oral solid dosage forms. In: Gibson M, editor. Pharmaceutical Pre-
formulation and Formulation. Colorado: Interpharm; 2001.
28. Gohel MC, Patel LD, Modi CJ, Jogani PD. Functionality testing of a coproc-
52
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
COMPRESSION PHYSICS IN THE FORMULATION DEVELOPMENT
53
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
S. PATEL, A.M. KAUSHAL, & A.K. BANSAL
45. Sheikh-Salem M, Fell JT. The tensile strength of tablets of lactose, sodium chlo-
ride, and their mixtures. Acta Pharm Suec. 1982;19:391–6.
46. Bos CE, Bolhuis GK, Van Doorne H, Lerk CF. Native starch in tablet formula-
tions: properties on compaction. Pharm Weekbl Sci. 1987;9:274–82.
47. Rees JE, Rue PJ. Time-dependent deformation of some direct compression ex-
cipients. J Pharm Pharmacol. 1978;30:601–7.
48. Oates RJ, Mitchell AG. Calculation of punch displacement and work of powder
compaction on a rotary tablet press. J Pharm Pharmacol. 1989;41:517–23.
49. Danielson DW, Morehead WT, Rippie EG. Unloading and postcompression
viscoelastic stress versus strain behavior of pharmaceutical solids. J Pharm Sci.
1983;72:342–5.
50. Rumpf H. The strength of granules and agglomerates. In: Knepper WA, editor.
Agglomeration. New York: Wiley Interscience; 1962.
51. Mashadi AB, Newton JM. The characterization of the mechanical properties of
microcrystalline cellulose: a fracture mechanics approach. J Pharm Pharmacol.
1987;39:961–5.
52. Kendall K. Agglomerate strength. Powder Metallurgy. 1988;31:28–31.
53. Hiestand EN. Dispersion forces and plastic deformation in tablet bond. J Pharm
Sci. 1985;74:768–70.
54. Hiestand EN. Mechanical properties of compacts and particles that control ta-
bleting success. J Pharm Sci. 1997;86:985–90.
55. Hiestand EN, Smith DP. Three indices for characterizing the tableting perform-
ance of materials. Adv Ceram. 1984;9:47–57.
56. Podczeck F, Newton JM. Calculation of the brittle fracture tendency (BFP) of
tablets. Int J Pharm. 2005;294:269–70.
57. Mufioz-Ruiz A, Villar TP, Justo A, Velasco V, Castellanos R. X-ray tablet and
raw diffraction as a method to study compression parameters in a direct com-
pression excipient, Compril®. Int J Pharm. 1996;144:147–52.
58. Khossravi D, Morehead WT. Consolidation mechanisms of pharmaceutical sol-
ids: a multi-compression cycle approach. Pharm Res. 1997;14:1039–45.
59. Amin MC, Fell JT. Comparison studies on the percolation thresholds of binary
mixture tablets containing excipients of plastic/brittle and plastic/plastic defor-
mation properties. Drug Dev Ind Pharm. 2004;30:937–45.
60. Kuentz M, Leuenberger H. A new theoretical approach to tablet strength of a
binary mixture consisting of a well and a poorly compactable substance. Eur J
Pharm Biopharm. 2000;49:151–9.
61. Rippie EG, Danielson DW. Viscoelastic stress/strain behavior of pharmaceuti-
cal tablets: analysis during unloading and postcompression periods. J Pharm Sci.
1981;70:476–82.
54
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
COMPRESSION PHYSICS IN THE FORMULATION DEVELOPMENT
55
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
S. PATEL, A.M. KAUSHAL, & A.K. BANSAL
79. Krycer I, Pope DG, Hersey JA. An evaluation of the techniques employed to in-
vestigate powder compaction behavior. Int J Pharm. 1982;12:113–34.
80. Takeuchi H, Nagira S, Yamamoto H, Kawashima Y. Die wall pressure meas-
urement for evaluation of compaction property of pharmaceutical materials. Int
J Pharm. 2004;274:131–8.
81. Jarosz PJ, Parrott EL. Effect of tablet lubricants on axial and radial work of fail-
ure. Drug Dev Ind Pharm. 1982;8:445–53.
82. Kikuta J, Kitamori N. Evaluation of the die wall friction tablet ejection. Powder
Technol. 1983;35:195–200.
83. Holzer AW, Sjorgen J. Friction coefficient of tablet masses. Int J Pharm.
1981;7:269–77.
84. Long WM. Die design and related questions in powder compaction. Spec Ceram.
1962;17:327–40.
85. Long WM. Radial pressure in powder compaction. Powder Metall. 1960;6:73–
86.
86. Adolfsson A, Gustafsson C, Nystrom C. Use of tablet tensile strength adjusted
for surface area and mean interparticulate distance to evaluate dominating bond-
ing mechanisms. Drug Dev Ind Pharm. 1999;25:753–64.
87. Eriksson M, Alderborn G. The effect of particle fragmentation and deformation,
the interparticulate bond formation process during powder compaction. Pharm
Res. 1995;12:1031–9.
88. Nicklasson F, Alderborn G. Analysis of the compression mechanics of pharma-
ceutical agglomerates of different porosity and composition using the Adams
and Kawakita equations. Pharm Res. 2000;17:949–54.
89. Kawakita K, Hattori I, Kishigami M. Characteristic constants in Kawakita's
powder compression equation. J Powder Bulk Solid Technol. 1977;1:3–8.
90. Heckel RW. Density-pressure relationships in powder compaction. Trans Metall
Soc AIME. 1961;221:671–5.
91. Heckel RW. An analysis of powder compaction phenomena. Trans Metall Soc
AIME. 1961;221:1001–8.
92. Ilkka J, Paronen P. Prediction of the compression behavior of powder mixtures
by the Heckel equation. Int J Pharm. 1993;94:181–7.
93. Danjo K, Ertell C, Carstensen JT. Effect of compaction speed and die diameter
on Athy-Heckel and hardness parameters of compressed tablets. Drug Dev Ind
Pharm. 1989;15:1–10.
94. Fell JT, Newton JM. Effect of particle size and speed of compaction on density
changes in tablets of crystalline and spray-dried lactose. J Pharm Sci.
1971;60:1866–9.
95. Paronen P, Juslin M. Compressional characteristics of four starches. J Pharm
56
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
COMPRESSION PHYSICS IN THE FORMULATION DEVELOPMENT
Pharmacol. 1983;35:627–35.
96. Kuny T, Leuenberger H. Compression behavior of the enzyme beta-
galactosidase and its mixture with microcrystalline cellulose. Int J Pharm.
2003;260:137–47.
97. Gabaude CM, Guillot M, Gautier JC, Saudemon P, Chulia D. Effects of true
density, compacted mass, compression speed, and punch deformation on the
mean yield pressure. J Pharm Sci. 1999;88:725–30.
98. Paronen P. Heckel plots as indicators of elastic properties of pharmaceuticals.
Drug Dev Ind Pharm. 1986;12:1903–12.
99. Rowe RC, Roberts RJ. Mechanical properties. In: Alderborn G, Nystrom C, edi-
tors. Pharmaceutical Powder Compaction Technology. New York: Marcel
Dekker; 1996.
100. Sun C, Grant DJ. Influence of elastic deformation of particles on Heckel analysis.
Pharm Dev Technol. 2001;6:193–200.
101. Monedero MC, Munoz-Ruiz A, Velasco-Antequera MV, Jimenez-Castellanos
Ballesteros MR. Constant compression-decompression stress rate profiles to ob-
tain rate dependence of maltodextrins for direct compression. Int J Pharm.
1996;132:183–8.
102. Kuentz M, Leuenberger H. Pressure susceptibility of polymer tablets as a critical
property: a modified Heckel equation. J Pharm Sci. 1999;88:174–9.
103. Walker EE. The properties of powder. Part VI. The compressibility of powders.
Trans Faraday. 1923;19:73–82.
104. Balshin MU. The theory about metallochemical processes. Vestnik Metalloprom.
1938;18:124–37.
105. Venkatesh GM, Coleman JN, Wrzosek TJ, Dubbu S, Palepu SR, Bandyopadhyay
R, Grant DJ. Fractional factorial designs for optimizing experimental conditions
for Hiestand's Indices of tabletting performance. Powder Technol. 1998;97:151–
9.
106. Hiestand EN. Rationale for and measurement of tableting indices. In: Alderborn
G, Nystrom C, editors. Pharmaceutical Powder Compaction Technology. New
York: Marcel Dekker; 1996.
107. Mullarney MP, Hancock BC. Improving the prediction of exceptionally poor ta-
bleting performance: an investigation into Hiestand's special case. J Pharm Sci.
2004;93:2017–21.
108. Podczeck F, Newton JM. The implications of the determination of the mechani-
cal strength of powder compacts containing a pre-formed hole. Powder Technol.
2003;132:10–15.
109. Alderborn G, Ahlneck C. Moisture adsorption and tabletting. III. Effect on tab-
let strength-post compaction storage time profiles. Int J Pharm. 1991;73:249–58.
110. Satoru W, Tomoko Y, Yoshifumi O, Masamitsu T. Development of a novel
compression tester and rheo-mechanical properties of wet-mass powder. II-
57
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
S. PATEL, A.M. KAUSHAL, & A.K. BANSAL
58
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
COMPRESSION PHYSICS IN THE FORMULATION DEVELOPMENT
125. Hancock BC, Zografi G. The relationship between the glass transition tempera-
ture and the water content of amorphous pharmaceutical solids. Pharm Res.
1994;11:471–7.
126. Kaushal AM, Gupta P, Bansal AK. Amorphous drug delivery systems: molecular
aspects, design, and performance. Crit Rev Ther Drug Carrier Syst. 2004;21:133–
93.
127. Rees JE, Shotton E. Effects of moisture in compaction of particulate material. J
Pharm Sci. 1971;60:1704–8.
128. Shotton E, Ganderton D. The tensile strength of compressed tablets: III. The
relation of particle size, bonding and capping in tablets of sodium chloride, aspi-
rin and hexamine. J Pharm Pharmacol. 1961;13 (Suppl.):144T–51T.
129. Shotton E, Rees JE. The compaction properties of sodium chloride in presence
of moisture. J Pharm Pharmacol. 1966;18 (Suppl.):160S–7S.
130. Bangudu AB, Pilpel N. Effects of composition, moisture and stearic acid on the
plasto-elasticity and tableting of paracetamol-microcrystalline cellulose mixtures.
J Pharm Pharmacol. 1985;37:289–93.
131. Garr JSM, Rubinstein MH. The influence of moisture on consolidation and
compaction properties of paracetamol. Int J Pharm. 1992;81:187–92.
132. Pande GS, Shangraw RF. Characterization of beta-cyclodextrin for direct com-
pression tableting: II. The role of moisture in the compactibility of beta-
cyclodextrin. Int J Pharm. 1995;124:231–9.
133. Pande GS, Shangraw RF. Characterization of beta-cyclodextrin for direct com-
pression tableting. Int J Pharm. 1994;101:71–80.
134. Nokhodchi A, Ford JL, Rowe PH, Rubinstein MH. The effect of moisture on
the Heckel and energy analysis of hydroxypropyl methylcellulose 2208 (HPMC
K4M). J Pharm Pharmacol. 1996;48:1122–7.
135. Nokhodchi A, Ford JL, Rowe PH, Rubinstein MH. The influence of moisture
content on the consolidation properties of hydroxy propylmethylcellulose K4M
(HPMC 2208). J Pharm Pharmacol. 1996;48:1116–21.
136. Shukla AJ, Price JC. Effect of moisture content on compression properties of
directly compressible high beta-content anhydrous lactose. Drug Dev Ind Pharm.
1991;17:2067–81.
137. Zografi G, Kontny MJ. The interactions of water with cellulose and starch-
derived pharmaceutical excipients. Pharm Res. 1986;3:187–94.
138. Tye CK, Sun CC, Amidon GE. Evaluation of the effects of tableting speed on
the relationships between compaction pressure, tablet tensile strength, and tablet
solid fraction. J Pharm Sci. 2005;94:465–72.
139. Ruegger CE, Celik M. The effect of compression and decompression speed on
the mechanical strength of compacts. Pharm Dev Technol. 2000;5:485–94.
140. Ruegger CE, Celik M. The influence of varying precompaction and main com-
paction profile parameters on the mechanical strength of compacts. Pharm Dev
59
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
S. PATEL, A.M. KAUSHAL, & A.K. BANSAL
Technol. 2000;5:495–505.
141. Armstrong NA, Palfrey LP. The effect of machine speed on the consolidation of
four directly compressible tablet diluents. J Pharm Pharmacol. 1989;41:149–51.
142. Ishino R, Yoshino H, Hirakawa Y, Noda K. Influence of tableting speed on
compactibility and compressibility of two direct compressible powders under
high speed compression. Chem Pharm Bull. 1990;38:1987–92.
143. Monedero MC, Jimenez-Castellanos Ballesteros MR, Velasco-Antequera MV,
Munoz-Ruiz A. Effect of compression speed and pressure on the physical char-
acteristics of maltodextrin tablets. Drug Dev Ind Pharm. 1998;24:613–21.
144. Larhrib H, Wells JI, Rubinstein MH. Compressing polyethylene glycols: The ef-
fect of compression pressure and speed. Int J Pharm. 1997;147:199–205.
145. Vezin WR, Khan KA, Pang HM. Adjustment of precompression force to reduce
mixing-time dependence of tablet tensile strength. J Pharm Pharmacol.
1983;35:555–8.
146. Akande OF, Rubinstein MH, Ford JL. Examination of the compaction proper-
ties of a 1:1 acetaminophen : microcrystalline cellulose mixture using precom-
pression and main compression. J Pharm Sci. 1997;86:900–7.
147. Jaffe J, Foss NE. Compression of crystalline substances. J Amer Pharm Ass Sci
Ed. 1959;48:26–9.
148. Sun C, Grant DJ. Improved tableting properties of p-hydroxybenzoic acid by
water of crystallization: a molecular insight. Pharm Res. 2004;21:382–6.
149. Bolhuis GK, Eissens AC, Zoestbergen E. DC calcium lactate, a new filler-binder
for direct compaction of tablets. Int J Pharm. 2001;221:77–86.
150. Lerk CF, Andreae AC, de Boer AH, Bolhuis GK, Zuurman K, de Hoog P,
Kussendrager K, van Leverink J. Increased binding capacity and flowability of
alpha-lactose monohydrate after dehydration. J Pharm Pharmacol. 1983;35:747–
8.
151. Fachaux JM, Guyot-Hermann AM, Guyot JC, Conflant P, Drache M, Veesler S,
Boistelle R. Pure paracetamol for direct compression Part I. Development of
sintered-like crystals of paracetamol. Powder Technol. 1995;82:123–8.
152. Nokhodchi A, Bolourtchian N, Dinarvand R. Crystal modification of phenytoin
using different solvents and crystallization conditions. Int J Pharm. 2003;250:85–
97.
153. Celik M, Ong JT, Chowhan ZT, Samuel GJ. Compaction simulator studies of a
new drug substance: effect of particle size and shape, and its binary mixtures
with microcrystalline cellulose. Pharm Dev Technol. 1996;1:119–26.
154. Sun C, Grant DJ. Influence of crystal structure on the tableting properties of
sulfamerazine polymorphs. Pharm Res. 2001;18:274–80.
155. Martino P, Guyot-Hermann AM, Conflant P, Drache M, Guyot JC. A new pure
60
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
COMPRESSION PHYSICS IN THE FORMULATION DEVELOPMENT
61
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
S. PATEL, A.M. KAUSHAL, & A.K. BANSAL
Technol. 1989;58:259–64.
172. Steendam R, Frijlink HW, Lek CF. Plasticization of amylodextrin by moisture;
Consequence for compaction behavior and tablet property. Eur J Pharm Sci.
2001;14:245–54.
173. Yoshinari T, Forbes RT, York P, Kawashiaki Y. The improved compaction
properties of mannitol after a moisture induced polymorphic transition. Int J
Pharm. 2003;258:121–31.
174. Kawashima Y, Cui F, Takeuchi H, Niwa T, Hino T, Kiuchi K. Improved static
compression behaviors and tablettabilities of spherically agglomerated crystals
produced by the spherical crystallization technique with a two-solvent system.
Pharm Res. 1995;12:1040–4.
175. Kawashima Y, Imai M, Takeuchi H, Yamamoto H, Kamiya K, Hino T. Im-
proved flowability and compactibility of spherically agglomerated crystals of
ascorbic acid for direct tableting designed by spherical crystallization process.
Powder Technol. 2003;130:283–9.
176. Morishima K, Kawashima Y, Takeuchi H, Niwa T, Hino T. Tableting properties
of bucillamine agglomerates prepared by the spherical crystallization technique.
Int J Pharm. 1994;105:11–8.
177. Di Martino P, Di Cristofaro R, Barthelemy C, Joiris E, Filippo GP, Sante M.
Improved compression properties of propyphenazone spherical crystals. Int J
Pharm. 2000;197:95–106.
178. Pawar A, Paradkar A, Kadam S, Mahadik K. Agglomeration of Ibuprofen with
talc by novel crystallo-co-agglomeration technique. AAPS PharmSciTech.
2004;5:e55.
179. Staniforth JN, Rees JE, Kayes JB, Priest RC, Cotterill NJ. The design of a direct
compression tablet excipient. Drug Dev Ind Pharm. 1981;7:179–90.
180. Jivraj M, Martini LG, Thomson CM. An overview of the different excipients
useful for the direct compression of tablets. Pharm Sci Tech Today. 2000;3:58–
63.
181. Shangraw RF. Compressed tablets by direct compression. In: Liberman HA,
Lachman L, Schwartz JB, editors. Granulation Pharmaceutical Dosage Forms:
Tablets Vol-1. 2 ed. New York: Marcel Dekker, 1989.
182. Habib Y, Augsburger L, Reier G, Wheatley T, Shangraw R. Dilution potential: a
new perspective. Pharm Dev Technol. 1996;1:205–12.
183. Moreton RC. Tablet excipients to the year 2001: A look into the crystal ball.
Drug Dev Ind Pharm. 1996;22:11–23.
184. Russell R. Synthetic excipients challenge all-Natural organics-offer advantages/
challenges to developers and formulators. Pharm Technol. 2004;27:38–50.
185. Reimerdes D, Aufmuth KP. Tabletting with Co-processed Lactose-Cellulose
Excipients. Manuf Chem. 1992;63:21–4.
62
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
COMPRESSION PHYSICS IN THE FORMULATION DEVELOPMENT
63
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
S. PATEL, A.M. KAUSHAL, & A.K. BANSAL
64
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
COMPRESSION PHYSICS IN THE FORMULATION DEVELOPMENT
65
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
View publication stats