Content uploaded by Arvind Kumar Bansal
Author content
All content in this area was uploaded by Arvind Kumar Bansal on Aug 12, 2014
Content may be subject to copyright.
Critical Reviews
TM
in Therapeutic Drug Carrier Systems, 23(1):1–65 (2006)
Compression Physics in the
Formulation Development
of Tablets
Sarsvatkumar Patel, Aditya Mohan Kaushal, &
Arvind Kumar Bansal
Department of Pharmaceutical Technology (Formulations),
National Institute of Pharmaceutical Education and Research
(NIPER), S.A.S.Nagar, India
Address all correspondence to Arvind Kumar Bansal, Department of Pharmaceutical
Technology (Formulations), National Institute of Pharmaceutical Education and
Research (NIPER), S.A.S. Nagar, Punjab-160 062, India;
akbansal@niper.ac.in or
bansalarvind@yahoo.com (A. K. Bansal)
Referee: Dr. Changquan Sun, Amgen, One Amgen Center Drive, MS 21-2-A,
Thousand Oaks, CA 91320-1799
ABSTRACT: The advantages of high-precision dosing, manufacturing effi-
ciency, and patient compliance make tablets the most popular dosage forms.
Compaction, an essential manufacturing step in the manufacture of tablets, in-
cludes compression (i.e., volume reduction and particle rearrangement), and con-
solidation (i.e., interparticulate bond formation). The success of the compaction
process depends not only on the physico-technical properties of drugs and ex-
cipients, especially their deformation behavior, but also on the choice of in-
strument settings with respect to rate and magnitude of force transfer. This re-
view discusses various properties of drugs and excipients, such as moisture
content, particle size and distribution, polymorphism, amorphism, crystal habit,
hydration state, and lubricant and binder level of the blend that have an influ-
ence on compaction. Tableting speed and pre/main compression force profile,
also have a bearing on the quality of the final tablet. Mechanistic aspects of ta-
bleting can be studied using, instrumented punches/dies, instrumented tablet-
ing machines, and compaction simulators. These have potential application in
pharmaceutical research and development, such as studying basic compaction
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
mechanism, process variables, scale-up parameters, trouble shooting problem
batches, creating compaction data bank, and fingerprinting of new active phar-
maceutical ingredients (APIs) or excipients. Also, the mathematical equations
used to describe compaction events have been covered. These equations de-
scribe density–pressure relationships that predict the pressures required for
achieving an optimum density. This understanding has found active application
in solving the analytical problems related to tableting such as capping, lamina-
tion, picking, sticking, etc. Mathematical models, force-time, force-distance, and
die-wall force parameters of tableting are used to describe work of compaction,
elasticity/plasticity, and time dependent deformation behavior of pharmaceuti-
cals. Various indices of tableting performance such as the bonding index, brittle
fracture index, and strain index can be used to predict compaction related prob-
lems. Compaction related physico-technical properties of commonly used ta-
bleting excipients have been reviewed with emphasis on selecting suitable com-
bination to minimize tableting problems. Specialized tools such as co-
processing of API and excipients can be used to improve their functionality.
KEY WORDS: compaction, consolidation, particle deformation, tablet ins-
trumentation, force-displacement profile
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 entities
4
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.
2
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
Pellet Powder
Capsules Film coating Tablets
Immediate release
Controlled release
• Spatial release
• Temporal release
Granules
FIGURE 1. Relationship between the various solid dosage forms.
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-
3
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
ess.
9
Particle size, size distribution, crystal habit, crystallinity, polymorphism,
pseudomorphism, amorphism, and crystal moisture are the most common ele-
ments that can change the compression properties.
10,11
Simple compression of a
bulk material, either powder or granulate, into a robust tablet is also influenced
by process variables such as force transfer, rate of force transfer, particle de-
formation behavior, and the adhesive forces between the particles.
12
The study of compression physics is of special interest in cases of high-dose
poorly compressible drugs that exhibit nonlinear relationship between com-
pression force and tablet tensile strength. These show a propensity towards ta-
bleting problems such as capping, lamination, sticking, and picking during scale-
up on high-speed tableting machines. As the deformation of pharmaceuticals is
time dependant, so reduced dwell times on high speed tableting machines in-
creases the chances of structural failure of tablets. In addition to varying the
type and proportions of composition, process-related factors also affect tablet
properties and quality.
6
Literature reports a number of high-dose and/or poorly
compressible drugs including paracetamol,
13,14
ibuprofen,
15
mefenamic acid,
16
acetazolamide,
17
metformin,
18
and hydroxyapetite.
19
The identification of tablet-
ing-related problems and establishing their relation with compaction parameters
such as compaction force, punch displacement, porosity, and tensile strength,
helps in understanding such complications and minimize them. For pharmaceu-
tical applications, the tablet ingredient mixtures are almost always complex and
it is as yet impossible to preview the properties of the end-product tablet by
knowing the exact composition of the powder mixture. Achieving the possibil-
ity of such predictions would be economic and time saving, and for this reason,
the characterization of model excipients and drugs, as well as several mixtures
of them, is an interesting and important research field.
20
II. PROPERTIES OF POWDERS
Physicotechnical properties of pharmaceutical solids dictate the performance
and processing of solid dosage forms, including their compressibility. These
properties are inter-related and a change in one property is likely to affect the
other.
II.A. Surface Properties
Surface properties of a powder material have a major influence on their flow
and intermolecular attraction. Atoms or ions located at a surface have a differ-
ent distribution of intermolecular and intramolecular bonding forces than those
4
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
present within a particle. This is caused by the unsatisfied attractive molecular
forces that extend out to some small distance beyond the solid surface. This
gives rise to free surface energy of solids, which plays a major role in interparticu-
late interaction.
21
Particulate attractive forces include those between like parti-
cles called cohesion, and those between un-like particles called adhesion.
22
The at-
tractive forces resist the differential movement of constituent particles when
subjected to an external force. Other types of resistance to relative movement
of particles include the electrostatic forces, adsorbed moisture, and residual sol-
vent on the surface of solid particles.
6
II.B. Porosity
The porosity of powder (E) is defined as the ratio of total void volume (V
v
) to
the bulk volume (V
b
) of the material.
4
The total void volume, V
v
is given by V
v
= V
b
- V
t
where, V
t
is the true volume.
E = V
b
- V
t
/ V
b
= 1 - V
t
/ V
b
(1)
One of the methods used to determine the compressibility of a powder bed is
the degree of volume reduction owing to applied pressure, which is related to
porosity and is assumed to be a first-order reaction.
23
Porosity–pressure rela-
tionship is also explained by the Heckel equation (discussed in Section VI.B.),
and is commonly used as a measure of compressibility.
24
II.C. Flow Properties
Good flow property of a pharmaceutical powder is essential to ensure proper
die fill during compression, especially in direct compaction process. Reasons
such as, high percentage of fines, excess moisture, lubricants, and electrostatic
charge may contribute to poor flow of powders.
25,26
Angle of repose is commonly used to measure flow of powders, and is the
maximum angle (Φ) between the plane of powder and horizontal surface. The
value of Φ less than 30° usually indicates free flowing material, up to 40°
indi-
cates reasonable flow potential, and above 50° the power flows with great diffi-
culty.
27
The increase in bulk density of a powder is related to its cohesivity. Bulk
density and tap density relationship is another way to index flowability.
27
Indices
such as the Hausner Ratio (H) and Carr’s Index (CI) are based on tapped and
bulk densities. Hausner ratio is the ratio of tapped density to bulk density,
27,28
and varies from about 1.2 for a free-flowing powder to 1.6 for cohesive pow-
ders.
27
5
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 Index
29
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.
I = [1 - V
t
/ V
0
] × 100 (2)
where, V
t
is the tap volume and V
0
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
6
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
Fragmentation Deformation Bonding
Solid
bridges
Undergo rearrangement to
form a less porous structure
Intermolecular force
(distance attraction
forces
)
Mechanical
interlocking
Elastic deformation
(Reversible)
Plastic deformation
(Irreversible)
FIGURE 2. The various steps involved in compaction of powders under
an applied force.
presented by Joiris et al.
7
They defined compressibility as the ability of a material
to undergo a reduction in volume as a result of an applied pressure and is repre-
sented by a plot of tablet porosity against compaction pressure; compactibility as
the ability of a material to produce tablets with sufficient strength under the ef-
fect of densification and is represented by a plot of tablet tensile strength
against tablet porosity; and tabletability as the capacity of a powdered material to
be transformed into a tablet of specified strength under the effect of compac-
tion pressure and is represented by a plot of tablet tensile strength against com-
paction pressure. The usage of this terminology is recommended, where all
three variables are considered in a single study.
The compaction process mainly includes particle rearrangement, followed
by deformation under pressure, although, smaller particles formed as a result of
fracture of larger particles may undergo further rearrangement.
1. Particle Rearrangement and Volume Reduction
The nonisostatic compression of powder or granular material to produce a
compact is a complex process, arising from the numerous internal processes
that lead to consolidation. These events include particle rearrangement, fracture,
and plastic deformation.
31
The first thing that happens when a powder is com-
pressed is that the particles are rearranged under low compaction pressures to
form a closer packing structure.
32
The finer particles enter the voids between
the larger ones and give a closer packing arrangement. In this process, the en-
7
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
ergy is evolved as a result of interparticulate friction and there is an increase in
the amount of particle surface area capable of forming interparticulate bonds.
33
As the pressure increases, further rearrangement is prevented and subsequent
volume reduction is accomplished by plastic and elastic deformation and/or
fragmentation of the particles.
31
The number of contact points known as poten-
tial bonding areas (inter- and intraparticulate) of the particles, are dependent on
particle size, size distribution, density, surface properties, interparticulate voids,
and process variables such as the moisture content, rate of flow, and the rela-
tionship between die-cavity diameter and particle diameter. Brittle particles are
likely to undergo fragmentation, i.e., breakage of the original particles into
smaller units resulting in increase in contact points. Plastic substances deform
in an irreversible manner, resulting in a permanent change of the particle shape
(irreversible process), whereas elastic substances when deformed resume their
original shape (reversible process).
The degree of volume reduction that a pharmaceutical powder bed under-
goes depends on the mechanical properties of the powder and the type of vol-
ume reduction mechanisms involved. Particle size and speed of compression
will in turn influence the mechanical properties of the material.
34
For example,
reduction in particle size has been related to a decreased tendency to fragment.
Some materials appear to have a critical particle size at which a transition from
brittle to ductile behavior occurs as the particles become smaller.
35
Brittle mate-
rials that undergo extensive fragmentation generally result in tablets of relatively
high porosity because of the large number of bonding points that are created,
which prevent further volume reduction. A ductile material, on the other hand,
will often result in tablets of low porosity because the high degree of plastic de-
formation enables the particles to move very close to each other. Similarly, dif-
ferent crystal habits such as spherical, cubical, and acicular, have different ten-
dencies to pack in a close structure.
10,13
Particles having regular shape appear to
undergo rearrangement more easily as compared to irregular particles.
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
8
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 (σ
f
). This stress is the fracture strength (Figure 3b). For duc-
tile/plastic materials, after a critical stress (σ
y
), 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.
Fracture
Strength
Yield
Strength
Stress
c1
c2
a b c
σ
f
σ
y
Strain
Fracture
Strength
E
E
E
FIGURE 3. Macroscopic stress-strain relationships showing, (a) reversi-
ble elastic deformation; (b) brittle behavior; and (c) ductile behavior (c1
normal plastic flow, c2 strain-hardening). E is the Young’s modulus.
9
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
TABLE 1. Deformation Mechanisms for a Few Representative Pharmaceuticals
Major deformation mechanism(s) Material
Fragmentation Ascorbic acid,
37
Dicalcium phosphate,
38
Maltose,
33
Phenacetin,
33
Sodium Citrate,
33
Sucrose
35
Fragmentation and elastic deformation Ibuprofen,
39
Paracetamol,
12,13,40
Fragmentation and plastic deformation Lactose monohydrate,
41,42
Microcrystalline cellulose
43
Plastic deformation Sodium bicarbonate,
44
Sodium chloride,
45
Pre
gelatinized starch
3
Elastic deformation Starch
46
3. Time Dependency of Compaction Process
Successful formation of a pharmaceutical tablet by the compression of solid
particulate matter depends on interparticulate bonding across particle–particle
interfaces. The areas of virtual contacts, during and after compression are ex-
pected to depend on the time-dependant flow of material, which occurs in con-
junction with instantaneously responding elastic deformation.
14
Some deforma-
tion processes (e.g., plastic deformation) are time dependent and occur at
various rates during the compaction sequence,
47
so that the tablet mass is never
in a stress/strain equilibrium during the actual tableting event. This means that
the rate at which load is applied and removed may be a critical factor. More
specifically, if a plastically deforming solid is loaded (or unloaded) too rapidly
for this purpose to take place, the solid may exhibit brittle fracture.
35
This is a
contributing factor to structural failure of tableting as the machine speed is
raised. Conversely, if the dwell time under the compression load is prolonged,
then plastic deformation may continue, leading to more consolidation.
5
Hence, the compact formation is determined by the time dependant vis-
coelastic behavior. Speed of the process (dwell time) can have marked effect on
compactibility and on tendencies such as lamination, capping, and picking,
which can occur during and/or after ejection.
48
Extended dwell time involves
application of compression force for a longer period of time. This further al-
lows plastic flow and absorbs the energy of elastic strain recovery before the
force is released.
14
Coupling of these processes results in viscoelastic behavior
being observed during the compression of the tablets at normal production
speed and often at slower speeds. The viscoelastic parameters of the tablets and
their components therefore are expected to be indicative of the relative sensitiv-
ity of tablet formation to the rates of compression and decompression and the
rate and the nature of ejection from die.
49
This can lead to a situation, where a
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
III. MODELS FOR MECHANICAL STRENGTH OF TABLETS
Different theoretical models for describing the mechanical strength of tablets
have been proposed in the pharmaceutical literature, some of which are re-
viewed below.
III.A. Bonding Mechanisms
The mechanical strength of a tablet depends on the dominating bonding
mechanism between the particles and the surface area over which these bonds
act.
33
When the surfaces of two particles approach each other closely enough,
their surface energies result in a strong attractive force, a process called cold
welding. This hypothesis is favored as a major reason for the increasing me-
chanical strength of a powder bed when subjected to compression force. On
the macro scale, most particles have an irregular shape, so that there are many
points of contact in the bed of powder. As the force is applied to the powder
bed, this transmission may result in generation of considerable frictional heat. If
this heat is not lost, the local rise in temperature could be sufficient to cause
melting of contact area of the particles, which would relieve the stress in that
particular region. In that case, the melt solidifies giving rise to fusion bonding.
6
“Rumpf bond summation concept” is based on the following types of
bonding mechanism, where the agglomerate strength is considered to depend
on the interparticulate bond structure,
50
a) Solid bridges (as a result of melting, crystallization, sintering, chemical re-
action, and binder hardening)
b) Bonding as a result of movable liquids (capillary and surface tension
forces)
c) Non freely movable binder bridges (viscous binder and adsorption layers)
d) Attraction between solid particles (molecular and electrostatic forces)
e) Mechanical interlocking (irregular particle size and size distribution)
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.
III.B. Bonding Surface Area
Bonding surface area is often used to define the effective surface area taking
part in the intermolecular attraction. In case of solid bridges, bonding surface
area is the true interparticulate contact area, whereas for intermolecular forces
the term is difficult to define. Considering the importance of the bonding sur-
face area for the mechanical strength, it is desirable to measure the actual sur-
face area participating in bonding. Hiestand described that the mixing of elastic
drug with plastic deforming material (e.g., MCC), resulted in a harder compact
as a result of plastic deformation increasing the bonding surface area.
53,54
Thus
during recovery, the stored elastic energy is inadequate to separate extensive ar-
eas of contact, and strong bonding results. However, direct measurements of
the bonding surface area are difficult. Instead, more indirect methods have been
applied, for example to measure the surface area of the powder and compare it
with the surface area of the tablet. Particle size, shape, fragmentation, deforma-
tion, and bond formation determine the bonding surface area in tablets.
33
Various techniques have been used to determine the extent of consolida-
tion and bonding mechanisms in pharmaceutical powders, such as stress relief
under pressure, three dimensionless tablet indices (brittle-fracture index),
55,56
X-
ray diffraction,
57
and multi-compression cycle.
58
III.C. Percolation Theory
The concept of percolation covers wide range of applications in pharmaceutical
technology and has been used with great interest in understanding the design
and characterization of dosage forms.
59
Different types of percolation such as
random-site, random-bond, random-site-bond, and continuum have been pro-
posed.
9
In the percolation theory, the tablet is seen as consisting of clusters of
particles forming a network. It has been used to describe the formation of the
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 substances
9
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. COMPRESSION CYCLE AND EFFECT OF APPLIED FORCES
Compression is important for molding a drug-excipient blend into tablets. The
compression cycle on a rotary tablet press includes precompression, main com-
pression, decompression, and ejection phases. To study the mechanism by
which powder materials are compressed, it is essential to study all stages of
compression cycle and to understand how various formulation and compres-
sion variables affect the finished tablet.
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.B. Main Compression
Main compression is the phase in which compression and consolidation of
powder bed occurs at high force. During main compression, the applied energy
is transformed into formation of interparticulate bonds. When a force is applied
in a die, the particles first undergo rearrangement to form a less porous struc-
ture at very low forces. Subsequently, the particles reach a state where further
relative movement is impossible, and an increase in the applied force induces
either particle fragmentation or deformation (or both). Viscoelastic properties
that determine compression behavior are functions of compression conditions
and thereby it may be useful to adjust compression conditions to avoid tablet-
ing problems.
61
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.
V.A. Attachable Instrumentation
Instrumentation for rotary machines includes strain-gauge punches and dis-
placement transducers for obtaining accurate measurement of the operational
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.
V.B. Fixed Instrumentation
Telemetric systems such as those just described, although capable of operating
at full factory speed, are inappropriate for monitoring routine production
batches. Although, the full compression force/distance profile is of great value
for research and development, it is not essential for routine monitoring. To ob-
tain this measurement, strain gauges can be mounted at various positions on
tablet presses to measure peak compaction forces on both the top and bottom
punches. The most accurate and convenient position for such strain gauges is
on the roll pin or the carriage pins.
In addition, there has been interest in measurement of the ejection force,
which, however is more difficult to measure than the compression force. The
exact position at which the head of a bottom punch makes contact with the
ejection cam depends on the position of the bottom pressure roll and shape
of the punch head. To measure the ejection force accurately using instru-
mented ejection cams, the system must be designed in such a way that the
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
V.C. Compaction Simulator
Compaction simulators are designed to mimic the exact cycle of any tableting
process and to record all important parameters during the cycle. The compac-
tion simulators have certain advantages such as mimicing the cycle of many
presses, and can be used for stress–strain studies. In addition to these advan-
tages, compaction simulators have potential application in pharmaceutical re-
search and development, such as studying basic compaction mechanisms,
processing variables, scale-up parameters, trouble shooting problem batches,
creating a compaction databank, and fingerprinting new drugs or excipi-
ents.
20,66
VI. PHYSICS OF COMPRESSION
The mechanics of tablets is very complex and a great deal of scientific effort
has been devoted to the analysis of the compaction of single component tablets.
It is therefore not surprising that most studies on mixtures deal with simple bi-
nary systems rather than more realistic multi-component mixtures.
60
The use of
instrumentation in tableting research offers an in-depth understanding of physi-
cal process of tableting. Force-time and force-displacement measurements can
be obtained from instrumented punches and dies. Later, this data can be fitted
to mathematical equations to elucidate the compaction behavior. The final qual-
ity attributes of a given blend can be understood better by using the parameters
obtained from the mathematical treatment of compaction data.
VI.A. Compaction Profiles
Compaction data obtained from instrumented tableting machine are basically of
two types—force-time and force-displacement profiles.
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
Time (ms)
Compression Force (kN)
Compression
Dwell
Time
Relaxation
b a c
b
a
FIGURE 4. Phases of compression event on a rotary tablet press, (a)
compression phase-horizontal and vertical punch movement; (b) dwell
time-only horizontal punch movement as plane punch head area is under
compression roller; and (c) decompression-both punches moving away
from upper and lower surfaces, initial relaxation of the tablet. (Adapted
from Ref. 38 with permission from Elsevier.)
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 (A
1
) and the compression slope (S
lc
) describe the
initial phase;
38
the area ratio (AR),
71
and the peak offset time (t
off
) characterize the
dwell time;
72
and the decompression area (A
4
) and the decompression slope (S
ld
) 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 roller
38
(Figure 4). The total area under the
force-time curve (A
tot
),
70
AR, t
off
, S
lc
, and A
1
are used for phase-specific alloca-
tion of the occurrence of plastic flow, which is found to be a function of com-
pression force
12
and moisture content.
39
Tablet strength,
73
tablet porosity, and
in-die bulk porosity
23
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 A
1
represents compression phase. For a constant tablet weight, A
1
is small for
powder having high density, (e.g., dicalcium phosphate dihydrate (DCP)) and
large for those having low density (e.g., MCC). Areas A
5
and A
6
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
A
1
A
2
A
3
A
4
A
5
A
6
Time
(
ms
)
Compression Force (kN)
FIGURE 5. Compression force-time curve for microcrystalline cellulose
(Avicel
®
PH102) showing, the compression phase (A
1
), the dwell time
phase (A
2
+A
3
), and decompression phase (A
4
). Areas A
5
and A
6
are ob-
tained by drawing a parallel line to X-axis from starting to the end point
of dwell phase, and the ratio (A
6
/A
5
) can be used to measure the plastic-
ity of a substance. (Adapted from Ref. 38 with permission 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
dwell-time coefficient (A
6
/A
5
) can be used to measure the plasticity of a substance
mixture.
38,74
Peak offset time, t
off
48,72
is the difference between the time of maximum pres-
sure and the middle of the dwell time (Figure 6). The duration of t
off
depends on
the ability of the compacted powder to relieve stress (time dependant plastic
flow)
70
and is an indication of the predominant mechanisms of particle defor-
mation during consolidation. At a given F
max
, short t
off
values are characteristic of
materials that consolidate mainly by brittle fracture whereas longer values indi-
cate an increase in plastic flow.
72
Hiestand found that materials that are known
to cap showed slow stress relaxation.
31
One of the reasons behind occurrence
of tableting problems on high speed rotary machines is the decrease in the plas-
tic flow
14,40
as indicated by a decrease in t
off
at faster machine speed. However,
Pressure (MPa)
Displacement (mm)
Stress relaxation
at constant strain
t
off
Time (ms)
FIGURE 6. Pressure-time and displacement-time profiles for microcrys-
talline cellulose (Avicel
®
PH 102) showing peak offset time, t
off
, an indica-
tion of stress relaxation at constant strain. (Adapted from Ref. 72 with
permission from Pharmaceutical Press, UK.)
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, (t
diff
) 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
F
max
Force (kN)
Time (ms)
t
diff
S
min
Displacement (mm)
A
I
A
II
FIGURE 7. Force-time and displacement-time curves for sorbitol (Karion
instant
®
) showing the time difference, t
diff
, between maximum force, F
max
and displacement at maximum densification S
min
. The area AI includes
the increase in force caused by densification and the decrease in force by
relaxation, whereas the area under the decompression curve, AII, is pre-
dominantly a measure of fast elastic expansion. (Adapted from Ref. 70
with permission from Elsevier.)
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 calculated
75
(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 = W
f
+ W
p
+ W
e
+ W
fr
(4)
where, W
f
is work against friction, W
p
is work of plastic deformation, W
e
is work of elastic
deformation, W
fr
is work of fragmentation, with W
e
≈ 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
Displacement (mm)
Force (kN)
Elastic
Deformation
Plastic Deformation +
Frictional Work
FIGURE 8. Force-displacement profile showing the plastic deformation
and frictional work, and the elastic deformation 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
TABLE 2. Mathematical Equations and Parameters to Study the Various
Aspects of Compaction of Powders
Process Parameter Ref.
Compaction stages
(compressibility and
consolidation)
Heckel equation
Kawakita equation
Leuenberger equation
Ge equation
Balshin equation
Work of plastic deformation
23,24,78
Elastic deformation,
Elastic recovery,
Capping/lamination tendency
Percentage elastic recovery
Work on upper punch in recompression
Elastic recovery index
Plastoelasticity index
Work of elastic deformation
Radial die-wall and axial pressure
71,79,80
Interparticulate bonding
Brittle fracture index
Bonding index
55
Plastic flow,
Plastic deformation
Work of plastic deformation
Yield pressure
Yield strength
23,71,77,78
Lubrication efficiency R value
Force transmission ratio
6,81
bonding.
77
Higher the compressibility of a material, lesser is the amount of
work needed to compress it to a certain final volume and vice versa. Hoblitzell
established the relationship between force-displacement and force-time
curves.
71
Moisture content of the blend also has a critical role in the energy in-
volved in the compaction.
39
Mathematical equations and parameters used to
study the various aspects of compaction of powders are summarized in Table 2.
3. Die Wall Force Profile
During tableting, friction arises between the material and the die (die-wall fric-
tion) and also between particles (interparticulate or internal friction). However,
internal friction is significant only during particle slippage and rearrangement at
low applied pressures. The friction between the powder mass and the die wall is
of concern beyond a certain consolidation ratio, when a sufficient radial pres-
sure gets generated.
82
The coefficients of friction related to the tableting process are static friction
coefficient (µ
1
), which gives the force required to initiate sliding, and dynamic
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 (µ
2
), which gives the force to maintain sliding between two
surfaces.
83
µ
1
= maximum axial frictional force/maximum radial force (5)
µ
2
= ejection force/residual die-wall force (6)
Friction phenomena can also be quantified by parameters calculated from up-
per and lower punch force and displacement. This includes the ratio of the
maximum lower punch force to the maximum upper punch force (called the
lubrication ratio or R value),
6
and the difference between the lower and upper
punch force, F
d
.
67
Radial pressure is another useful parameter for predicting compaction be-
havior of pharmaceuticals.
84,85
Figure 9 shows the force and punch displacement
profile corresponding to compression, decompression, and ejection. The die
Time (ms)
Force
(
kN
)
Punch dis
p
lacement
(
mm
)
Force Profiles and punch displacements
Tableting
Process
FIGURE 9. Force and punch displacements profiles during tableting
process. (Adapted from Ref. 80 with permission 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
VI.B. Compaction Equations
A compaction equation relates some measure of the state of consolidation of a
powder, such as porosity, volume (or relative volume), density, or void ratio, as
a function of the compaction pressure. Since the recording of first-ever accu-
rate compaction data in 1923 by Walker, a number of compaction-related equa-
tions have been proposed. However, the Heckel and Kawakita equations have
been the most commonly used, as they relate the physical properties of the ma-
terials to applied pressure.
24
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
Pa/C = [1/ab + Pa/a] (7)
C = [V
0
– V/V
0
] (8)
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 V
0
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 model
90,91
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
ln[1/(1-D)]
A
B
D
a
D
0
Compression Pressure (MPa)
Region II Region I Region III
FIGURE 10. A typical Heckel plot derived from relative density and
compaction pressure. Region I corresponds to particle rearrangement at
low pressure, whereas region II, the linear part of the curve shows the
ability of the material to deform plastically. At higher pressures, region
III is observed due to work hardening. D
a
gives densification due to ini-
tial particle rearrangement, whereas D
0
gives densification due to initial
die filling. (Adapted from Ref. 13 with permission 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, P
y
. 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 (D
a
)
A = ln [1/1–D
0
] + B (10)
D
a
= 1 – e
-A
(11)
where, ln [1/1–D
0
] is related to the initial die filling and B is the densification as
a result of slippage and rearrangement of primary and fragmented particles (D
B
). B
From the point B where the Heckel Plot intercepts the Y-axis, D
0
is ob-
tained (zero pressure powder density), which is defined as the densification as a
result of die filling or initial powder packing.
D
0
= 1 – e
-B
(12)
D
B
= D
A
– D
0
(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 observed
97,98
(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) hardening
97,99
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 Rowe
74
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 = [Py
2
- Py
1
/Py
2
] 100
(15)
where, Py
1
is the yield pressure at low speed and Py
2
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 Leuenberger
102
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.
()
⎥
⎦
⎤
⎢
⎣
⎡
⎟
⎟
⎠
⎞
⎜
⎜
⎝
⎛
−
−
−−−=
c
cc
C
ρ
ρ
ρρρσ
1
1
ln1
1
(16)
where, σ is the pressure, ρ is the relative density, ρ
c
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 Paronen
92
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 equation
103
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
′
/ V
0
+ C
1
(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
where, V
0
is the volume at zero porosity. The relative volume is V
′
/V
0
= V =
1/D, C
1
is constant. The coefficient L is referred to as the pressing modulus.
104
The Heckel and the Walker equations transform the relative density in a dif-
ferent manner (Figure 11). The Heckel transformation is practically linear at in-
termediate densities, whereas Walker transformation is most curved in this re-
gion. At high densities the Walker equation approximates linearity whereas the
Heckel transformation tends to infinity. Compared with the Walker equation
the Heckel model is less reproducible and has less discriminative power as a
general compression constant.
23
VI.C. Tableting Indices
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-
FIGURE 11. Heckel and Walker transformations of relative density.
Heckel transformation is linear at lower densities, whereas Walker is lin-
ear in the high density region. (Adapted from Ref. 23 with permission
from Elsevier.)
ln[1/(1-D)]
10
-(1/D)
Relative Density
Heckel
Walker
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
tionship, another approach to characterize the properties of compact is by di-
mensionless Hiestand’s indices,
55
which gives insight about relative tableting
performance of materials. Hiestand also defined and developed procedures for
determining the indices of tableting performance such as bonding index (BI), brit-
tle fracture index (BF), and strain index (SI).
55
The determination of these three in-
dices involves measurements of indentation hardness and tensile strength of
large compacts with a hole and without a hole in the center.
56
BI estimates the survival of bonds during decompression. Materials with
higher BI form stronger compacts which survive the die-wall and ejection
forces. Conversely materials with low BI may produce friable tablets. The values
of BI generally range from 0 to 0.04.
105
BFI indicates the ability (or inability) of
material to relieve localized stresses within the compact by plastic deforma-
tion.
105
A BFI of 1 would correspond to purely brittle material, whereas a zero
value indicates that stress at the whole had been completely relieved by plastic
deformation.
27
Hiestand and Smith proposed that the materials with high BFI
would be less able to relieve stresses during decompression and ejection and
therefore be more susceptible to capping and lamination. Problems crop up
when BFI is 0.8 or more.
55
SI indicates the relative strain energy change (or a
change in size) during elastic recovery after plastic deformation. The values
range from 0 to 0.04 and a high SI value shows potential structural failure in
terms of capping and lamination as a result of high elastic recovery after de-
compression.
105
According to Hiestand, special case materials do not plastically
deform and are believed to be exhibit poor tableting performance.
106
Such ma-
terials are identified when the compression stress required to form a compact
(σ) is greater than its dynamic indentation hardness (H
0
), i.e., σ/H
0
is greater than
unity. For normal materials that show plastic flow, σ/H
0
is less than unity.
107
Podczeck and Newton have criticized the concept of BFI and stated that
the calculations as described by Hiestand et al.
31
with cubic compacts and ap-
plied to circular tablets from data using the value of the tensile strength of tab-
lets with and without a central hole, are incorrect based on formula used to cal-
culate the tensile strength of the tablets, which had a central hole. Hence, it is
essential to know the stress conditions, which exist in the specimen.
56,108
VII. FACTORS INFLUENCING THE COMPACTION OF
PHARMACEUTICAL POWDERS
The identification and quantification of the numerous parameters that affect
the compaction process are vital for product uniformity. Crystal habit, particle
size, particle size distribution, polymorphism, amorphism, moisture content,
salt form, tableting speed, (dwell time, lag time), mechanism by which particles
undergo compaction, solid state of lubricants and their concentration, coproc-
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
essing of excipients or drugs, pre- and main-compression force profile, granu-
lation methods, and ultrasonic vibration, all are known to affect the compaction
of pharmaceutical powders. All these factors are interrelated to each other and
cannot be considered in isolation. The various factors, by acting at the funda-
mental level, have the ability to influence the behavior of powder under com-
paction. For example, moisture level is a determinant of the plasticity of a
blend; force profile may influence viscoelastic behavior; and solid state forms
may dictate particle rearrangement based upon differential slip plane character-
istics. Also, in the following discussion, at times certain conflicting results have
been mentioned, this can be attributed to the different experimental designs
and conditions used in one study to the other.
VII.A. Moisture Content
The study of moisture adsorption and absorption by excipients and solid dos-
age forms provides information for selecting excipients such as disintegrating
agents, direct-compression carriers, binders, and for determining the humidity
control required during production and storage.
109
Moisture affects the flow,
29
mixing rheology,
110
compaction,
39,111
true density,
43
and mechanical properties of
granules as well as tablets.
73
Water plays a key role in all manufacturing steps,
therefore, water–powder interaction is a major factor in the formulation, proc-
essing, and performance of solid dosage forms.
112
The amount of water associ-
ated with a solid at a particular RH and temperature depends on its chemical af-
finity, surface area, and available sites of interaction.
113
Moisture plays an important role in interparticulate bond formation by en-
hancing the tensile strength of the powder bed and decreasing the density varia-
tion within the tablet. The reduction in tablet density variation is ascribed to the
lubrication of the die wall, which allows more of the applied force to be trans-
mitted through the compact onto the lower punch (R value).
67
Absorbed water
decreases particle surface free energy and tablet adhesion to the die wall. Any
water expressed during compaction also functions as a low-viscosity lubricant.
Rees and co-workers found in their study that lower applied pressure is re-
quired in presence of moisture to improve powder compaction.
73
MCC is an important excipient upon which, the role of moisture has been
extensively investigated. Teng et al. reported that tablets containing MCC be-
came harder as the moisture content increased,
114
whereas a lack of moisture
was responsible for tablet lamination because of increased yield force and elas-
tic recovery.
115
In another study, Pilpel and Ingham reported the effect of mois-
ture in MCC on density, compaction, and tensile strength and related the
changes in mechanical properties of MCC to the way in which water is sorbed
into the cellulose structure.
116
A marked reduction in MCC tablet tensile
strength was observed at 8% w/w water content by Fassihi and co-workers.
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
This effect was attributed to hydrostatic resistance to consolidation caused by
the presence of water in a relatively unrestricted form.
117
The effect of moisture
on the binary mixtures of MCC-PVP also has been investigated.
118
Pilpel and
Ingham concluded that moisture is sorbed into the amorphous part of MCC
119
and most likely exists in at least three states—tightly bound to an anhydroglu-
cose unit (one water molecule binding between two anhydroglucose units, fol-
lowed by each anhydroglucose unit), less tightly bound, and bulk water.
120
In-
creases in the molecular mobility of MCC explained how water acted as a
plasticizer in amorphous part of MCC. Also, MCC with low moisture content
(1.1%) yields lower tablet strength than normal moisture content (4.9%). Com-
mercial grade Avicel
®
PH-101 and Emcocel
®
MCC showed 20–30% increase in
cohesiveness after addition of water, which did not increase further with addition
of more water. Khan et al. also examined the effect of MCC’s moisture content
on the compression properties of formulations containing paracetamol and po-
tassium phenethicillin and reported that the strongest compacts were produced
with MCC having 7.3% moisture.
121
Table 3 gives examples of the effect of mois-
ture on compaction for a few representative drugs and excipients.
An increase in tensile strength with increasing moisture content or RH has
been explained by adsorbed water functioning as a surface-restructuring me-
dium, thus increasing the amount of solid bridges.
122
Another possible explana-
tion for increasing tensile strength is that immobile water layers sorbed at parti-
cle surfaces can enhance particle–particle interaction. According to this theory,
an adsorbed water vapor layer can contribute in two ways-(i) tightly bound wa-
ter vapor layers can be regarded as part of the particles that reduce interparticu-
lar surface distances and increase intermolecular attraction forces,
122
and (ii) ad-
sorbed layers can touch or penetrate each other, thus increasing the attractive
forces between neighboring particles.
123
Additionally, moisture in a material ex-
erts the van der Waals’ forces, and aids in the development of additional bonds
by plastic deformation and/or melting or recrystallization of powder particles.
A contrary effect of decrease in tensile strength upon increased moisture is at-
tributed to the formation of water layers or the presence of free water at the
surfaces, which reduces intermolecular attractive forces and allows separation
of the particles.
39,122
An alternative explanation for the effects of moisture on the compaction
involves the glass transition temperature (T
g
) of amorphous materials, which re-
duces due to the plasticizing effect of water and changes the viscoelastic
properties of polymers.
124–126
At certain moisture content above the level
consistent with the transition from the glassy to the rubbery state, significant
changes occur in the mechanical properties of the polymer. At temperatures ex-
ceeding T
g
, polymers exhibit highly increased chain mobility and plasticity,
which have major consequences for compaction properties. Therefore, water is
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
TABLE 3. Effect of Moisture on Powder Compaction for a Few
Representative Drugs/Excipients
Key: HPMC = hydroxypropyl methylcellulose
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
VII.B. Compression Force Profile
It is well known that speed of compression can have significant effect on the
compaction properties of pharmaceutical powders and this is a challenge during
Drug/excipient Observations Ref.
Maltodextrin
Compact exhibited highest tensile strength at 8% mois-
ture and above this level, tensile strength was decreased
as a result of reduction in interparticulate adhesion.
111
(lower degree of
polymerization)
Sodium chloride 10% Moisture exerted a hydrodynamic resistance to
consolidation, which inhibited interparticulate shear
forces and bonding
127-129
Paracetamol and
paracetamol–
cellulose
6% Moisture content in paracetamol, and 2–4% in
paracetamol-cellulose formed stronger tablets than
those without moisture
130,131
Ibuprofen 2.5% Moisture increased the particle interaction and al-
lowed plastic flow under applied pressure.
39
β-cyclodextrin β-Cyclodextrin lost its compactibility on removal of wa-
ter, and about 14% appeared optimum for maximum
compactibility.
132,133
HPMC
*
and
HPMC-ibuprofen
At all compression speeds, an increase in moisture con-
tent reduced the elastic recovery of compacts due to
greater tablet consolidation.
134,135
Anhydrous β-
lactose
An increase in the moisture content reduced tablet
hardness and greater pressure was required to achieve
specified hardness values.
136
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
scale-up and technology transfer when tableting speeds increase significantly.
138
Altering the method of force application is beneficial for tablet production in
order to increase tablet strength and prevent the incidence of capping and lami-
nation. In all cases, for a given pressure, double compaction produces stronger
tablets than single compaction. The ratio and magnitude of pre- and main com-
paction pressures can be varied depending on the deformation behavior of ma-
terials.
138
DCP/MCC and pregelatinized starch
139
tablets show no significant
difference in crushing strength values regardless of whether the precompaction
pressure is less than or greater than the main compaction pressure. However,
both direct compression acetaminophen and ibuprofen were found to have in-
creased crushing strengths and decreased capping/lamination when the pre-
compaction pressure was less than the main compaction pressure. When the
time interval between the pre- and main compaction events was varied from 30
to 500 msec, no significant difference in the crushing strength or capping/
lamination tendency was observed.
140
For maize starch and polymeric materials (plastic), an increase in the yield
pressure with punch velocity is attributable to a change from ductile to brittle
behavior or a reduction in the amount of plastic deformation due to the time-
dependent nature of plastic flow. However, for magnesium and calcium car-
bonates (brittle), no changes in yield pressures were observed with increasing
punch velocity.
74
In another study, describing the reduction in porosity of sub-
stances that consolidated principally by fragmentation, relatively little velocity
dependence was observed.
141
For pure lactose tablets, the porosity and tensile
strength of compacts were less affected by compression rate, though they de-
pended on the applied force.
138
The properties of MCC tablets varied with the
tableting speed, in addition to the applied force, as a result of its time depend-
ant plastic deformation.
142
However, Tye et al. reported that the tableting of
MCC was reported to be speed independent.
138
Similar contrasting results have
also been reported for DCP. The tabletability of DCP was reported to be inde-
pendent of machine speed,
47,141
but the recent published literature by Tye et al.
showed that tabletability of DCP increased as the compaction speed was in-
creased. It is interesting to note that stronger tablets were formed at higher tablet-
ing speed (shorter dwell-time) under similar compaction pressure.
138
These differ-
ences could be explained by the range of compression pressure or tableting speed
explored in various studies. Tye et al. had explored at much broader range, as
compared to previous studies reported by Rees et al.
47
and Armstrong et al.
141
Higher tableting speeds, cause extensive fragmentations of DCP, resulting in
larger number of new bonding sites available for the bonding.
138,34
In case of maltodextrin, mechanical parameters and disintegration time in-
creased as applied pressure was increased above 90 MPa, however, no differ-
ences were found above this limit.
101,143
Various grades of polyethylene glycol
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
(PEG) (molecular weight 1500 to 35000) showed that resistance to densifica-
tion increased with molecular weight and compression speed. At any compres-
sion speed, low molecular weight PEGs undergo greater densification. For a
given molecular weight, tablets made at 10 mm/s had better mechanical
strength than those made at 300 mm/s. PEG 12000 gave the hardest tablets at
all compression speeds, but compressibility was lesser than lower molecular
weight PEGs.
144
Vezin et al. described that adjustment of pre- and main compression re-
duced the loss of tablet tensile strength arising from lubricant over-mixing.
145
The duration of t
off
depends on the ability of the compacted powder to relieve
stress and is an indication of the predominant deformation during consolida-
tion. Thus, at a given maximum pressure (P
max
), short t
off
values are characteristic
of materials that consolidate mainly by brittle fracture whereas longer values in-
dicate an increase in plastic flow. t
off
decreases with increase in P
max
as a result of
the reduction in the porosity of the compact and consequent restriction of plas-
tic flow into the void spaces.
72
Blend of paracetamol and MCC (1:1) was compacted at different combina-
tions of pre- and main compression of 320 and 240 MPa. Tensile strength de-
creased when compression speed was increased. Precompression played a major
role at high compression speeds as the tensile strengths of tablets at precompres-
sion of 160 MPa followed by a main-compression of 80 MPa (at 390 mm/s) were
similar to those compressed using a single compression of 320 MPa at the same
compression speed.
40
Thus, combinations of lower pressures can be employed to
compress the material to the same tensile strength as a
high single compression.
146
Also, the tableting speed affects dwell time and lag-time, which ultimately affect
the time dependent deformation behavior of the pharmaceuticals. Another study
by same investigator reported that the application of higher dwell-time resulted in
greater tensile strengths than lag-time, which had lesser effect on the compaction
properties.
14
VII.C. Solid-State Properties
Drugs and excipients used in tableting exist in a variety of solid-state forms.
These forms often show difference in their physico-technical behavior, there-
fore, it is important to know their influence on pharmaceutical process includ-
ing compaction.
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
when water of crystallization is removed (e.g., ferrous sulfate heptahydrate).
147
The influence of water in the crystal structure on the compaction properties of
structurally similar crystals, p-hydroxybenzoic acid anhydrate (HA) and mono-
hydrate (HM) were investigated. Incorporation of water into the crystal lattice
resulted in greater tablet strength and larger volume reduction as a result of im-
proved plasticity. In case of HA crystal compression, the zigzag-shaped layers
mechanically interlock, inhibiting slip and reducing plasticity. However, in the
HM crystals, a water molecule played a space-filling role, which increases the
layer separation and allows easier slip between layers and provides greater plas-
ticity to HM crystals, which increases the interparticulate bonding surface
area.
148
In another study, the compaction properties of calcium lactate pentahydrate
were found to be much better than calcium lactate trihydrate. Moreover, as a
crystalline structure, calcium lactate pentahydrate showed compaction speed
sensitivity. This meant that, in combination with its excellent flow properties,
calcium lactate pentahydrate was a suitable filler-binder in tablets prepared by
high-speed compaction.
149
Lactose monohydrate, however, showed improved
tablet strength upon removal of water of crystallization by thermal or chemical
means.
150
Organic solvents converted α-lactose monohydrate into a stable an-
hydrous product with increased binding capacity and flowability.
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.
4. Particle Size and Particle Size Distribution
The particle size and particle size distribution can affect both the particle rear-
rangement and compaction phases. Correlations between average particle size
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
VII.D. Salt Form
Another important but rarely explored factor determining the compaction
properties, is the salt forms of pharmaceuticals. Sun and Grant examined the
effects of salt form of L-lysine with the following anions at various pressures-
acetate, monochloride, dichloride,
L-aspartate, L-glutamate (dihydrate), and L-
lysine (zwitterionic monohydrate). Results indicated that different salts were dif-
fering in their compaction behavior and melting temperature of each salt was
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
found to be as an indicator of its tensile strength at zero porosity. Because a
higher melting point indicates stronger intermolecular and interionic interac-
tions in the crystals, the tensile strengths at zero porosity might be related to the
melting points of the salts.
160
VII.E. Granulation Method and Binder
As a result of poor flowability and compaction behavior, pharmaceutical pow-
ders are often subjected to granulation prior to tableting. The optimal granula-
tion method is selected for production of porous and free-flowing granules,
which enable formation of tablets with high mechanical strength at low com-
pression pressures.
In an attempt was made to study the effects of different wet and melt
granulations on compaction. In the wet granulation methods, the tensile
strength was in the order of wet massing granulation > wet fluidized bed granu-
lation > wet tumbling fluidized bed granulation > wet high-speed mixer granu-
lation; and melt high-speed mixer granulation > melt fluidized bed granulation
> melt tumbling fluidized bed granulation in melt granulation. These results in-
dicated that the compactabilities of granules varied with the granulation method
used.
161
In an independent study, melt granulations of lactose and PEG 4000
were made with a fluid-bed granulator and for comparison in a high-speed
mixer with scraper. Remarkable differences in tablet properties such as hard-
ness and disintegration time were found between the two different mechanisms
(coalescence and layering) of granule formation.
162
The effect of binder on the relationship between the bulk density and com-
pactibility of lactose granulations was studied by comparing binderless granules
(α-lactose monohydrate) with granules (β-lactose) containing hydroxylpropyl
cellulose. The results showed that the effect of binder on tablet strength was
independent of the type of lactose used, but was significantly influenced by the
consolidation and compaction behavior of the lactose particles. The effective-
ness of the binder increased with a decrease of the bulk density of the granule
powder bed. Tablets with a high crushing strength could be prepared from po-
rous granules, containing a binder.
163
The effect of wax (glyceryl behenate) on
the deformation and compression characteristics of MCC and acetaminophen
prepared by extrusion and spheronization were described. Beads made without
wax required greater compression forces to form cohesive tablets. As the
amount of wax in the bead formulation was increased, the beads became more
plastic and compressible. The Heckel analysis showed that as the level of wax in
the bead formulation was increased, the yield pressure decreased, indicating that
the beads densify by a plastic deformation mechanism.
164
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
VII.F. Use of Ultrasonic Vibration
Levina et al. found that coherent ibuprofen tablets could be prepared by ultra-
sound-(US) assisted compaction at pressures as low as 20-30 MPa. The break-
ing forces of the tablets produced with ultrasound applied during compaction
were found to be consistently significantly higher than when compaction was
performed conventionally, or with US applied before or after compaction. Ap-
plication of US during compaction made it possible to increase tablet mechani-
cal strength by 2–5 times.
165
In another study by the same author, it was re-
ported that coherent paracetamol tablets could be prepared by US-assisted
compaction at similarly low pressures. The breaking forces of the tablets pro-
duced with US applied during compaction were higher than those produced
conventionally.
166
The explanation provided for enhanced compactibility was
that US improves particle rearrangement and provides energy for partial melt-
ing and subsequent fusion of particle surfaces, which increases interparticulate
bonding. Development of solid bridges between the particles during US-
assisted compaction was thought to result in a reduction of void space.
166
VIII. TABLETING PROBLEMS
Compression related tableting problems mainly include capping/lamination and
sticking/picking. These problems stem from poor compactibility at the particu-
late level and thereby an in-depth scrutiny of the compaction behavior can aid
in scientifically absolving the respective problem. Capping is a term used to de-
scribe the partial or complete removal of the top or bottom crown of a tablet
from the main body whereas lamination is the separation of a tablet into two or
more distinct layers. These tableting problems though usually arise immediately
after compaction, may surface after a lag time. Friability test is the quickest way
of revealing such a problem. The main reason behind these problems is the in-
ability of materials to relieve stress after the removal of force.
55
Also, excess
fines can trap air in the tablet resulting in capping and lamination. The inherent
deformation properties of the material, such as plastic, brittle or elastic also af-
fect these tableting problems. Density and stress are unequally distributed in a
compact and elastic recovery is considered to be the most likely cause of cap-
ping in the areas of high density.
167
During compression, particles undergo suf-
ficient plastic deformation to produce die-wall pressure greater than that can be
relieved by elastic deformation. Sometimes die-wall pressure produces enough
stress inside the compact that leads to cracking or surface fracture upon ejec-
tion. Tablets that do not fracture after decompression relieve internal stress by
plastic deformation. As the plastic deformation is a time dependant phenome-
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.
IX. IMPROVEMENT OF COMPACTION BEHAVIOR
Many of the pharmaceutical drugs and excipients per se exhibit poor com-
pressibility. Depending upon what constitutes the major bulk of the blend, im-
portance needs to be given either to improving the compaction behavior of ei-
ther the API or the excipient(s). In addition, steps such as granulation and
coprocessing may be required, to introduce satisfactory compactibility. Low
dose drugs with poor compressibility rarely show tableting problems, because
excipients contribute the required compressibility. However, for high dose
drugs, improvement of the API and/or selection of excipients especially the
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).
IX.A. API Modification
Modification of the API is essential for high dose drugs because of the limited
role excipients play in improvement of compactibility. Production of spherical
crystals to improve compaction behavior and flow has recently received atten-
tion. Spherical crystals of acebutolol hydrochloride,
174
ascorbic acid,
175
bucil-
lamine,
176
and propyphenazone
177
showed improved compactibility and flow
properties. The improvement of static compression behaviors of the agglomer-
ated crystals was due to higher stress relaxations and lower elastic recoveries of
agglomerated crystals.
174
The excellent compactibility of agglomerates was also
attributed to the fragmentation property and a greater degree of plastic defor-
mation under compression.
176
Pawar et al. described some techniques for crystal
coagglomeration to obtain ibuprofen-paracetamol agglomerates.
15,178
Optimiza-
tion of tableting behavior of excipients was carried out by Staniforth and group.
They examined alternative crystallization conditions in order to design a directly
compressible mannitol and obtained a highly porous surfaced mannitol.
179
IX.B. Excipient Modification/Selection
The type and amount of the excipient(s) selected influence the overall quality
attributes of the tablets. From view point of their role in compaction, excipients
may be classified as (i) those that have a positive influence, such as diluents and
binders; and (ii) those with negative influence such as disintegrants, and lubri-
cants. Various classes of excipients with emphasis on their respective roles in
compaction are discussed in the following section.
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
MCC
51
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
contributes positively towards, compact strength, even in the absence of frag-
mentation. MCC has both the properties and is considered best diluent for di-
rect compression. Materials undergoing extensive fragmentation acquire a large
number of interparticulate contact points. The latter, despite a low compaction
load per unit area, are sufficient to generate a strong compact by virtue of their
large number. In contrast, less fragmenting materials such as crystalline lac-
tose,
94
acquire only a small number of contact points that will give a good com-
pact, only if interparticulate bonds are strong enough or solid bridges are formed.
Successful tablet production therefore depends upon optimum balance be-
tween brittle fracture and plastic behavior, as dictated by the compression char-
acteristics of the API and excipients. The most commonly employed excipients
ranked in ascending order of their brittleness are MCC, spray-dried lactose, β-
lactose, α-lactose, α-lactose monohydrate, and DCP.
180
A compilation of com-
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
TABLE 4. Commonly Used Tableting Diluents and Their Compaction Properties
Diluent Features Ref.
High plastic deformation
Microcrystalline
cellulose
32,116,186
Excellent compactibility at low pressures
High dilution potential, most useful diluent for direct compression
Self-lubricating property
Undergoes brittle fracture with low fragmentation
α-Lactose 41,187
monohydrate
Not directly compressible, used in wet granulation
Consolidates by particle fragmentation with low fragmentation
Anhydrous
187,188
β-lactose
Directly compressible, poor flowability, picks up moisture at ele-
vated humidities
Binding capacity of anhydrous form higher than monohydrate
Plastic nature provides better compaction than crystalline lactose
Spray-dried
94,185
lactose
Requires high compression pressures
Compressibility adversely affected below 3% moisture
High dilution capacity and freely flowing
Bonding not affected by addition of lubricants
Deforms by brittle fracture with high fragmentation
Dibasic calcium
phosphate
186,189
Lubricants, as MS, have practically no effect on binding
dihydrate
Deforms by brittle fracture
Dibasic calcium
phosphate
190
Unlike the dihydrate, anhydrous form exhibits capping/lamination
at higher pressure
anhydrous
Poorly compressible
Starch 46,95
Highly sensitive to lubricants
Good disintegrant, binder
Next choice after lactose and MCC
Pregelatinized
starch
Good compressibility and high dilution capacity than native starch
Extremely sensitive to the softening effects of alkaline stearates
Higher concentrations of MS (above 0.5% w/w), can affect inter-
particulate bonding, stearic acid is the preferred lubricant
Good binder, free flowing, good disintegrant properties
191-193
Sorbitol
Deforms by fragmentation
Different crystalline types (α, β, γ, and δ) and amorphous forms
are known, δ form is most stable and has the best compaction
2% MS tablet formulation has no negative effects on tablet
strength
Hardening of tablets upon ageing caused by recrystallization of
sorbitol can be prevented by adding pregelatinized starch
194-196
Mannitol
Deforms by brittle fracture, nonhygroscopic, useful for moisture-
sensitive drugs
Several polymorphic forms such as β and γ differ in compression
behavior
173,197
Dextrose and
modified dextrose
(Dextrates)
Deforms by brittle fracture, used as a direct compression diluent
Less hydroscopic and produces softer tablets than lactose
Hydrous form incompatible with moisture sensitive drugs
More browning of tablets in presence of amines than lactose
Dextrates are made by addition of other carbohydrates at lower
concentrations. Good for direct compression and free flowing.
198,199
Key: MCC, microcrystalline cellulose; MS, magnesium stearate
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
combining two or more excipients by an appropriate process, leading to forma-
tion of an excipient with superior physico-technical properties, without any as-
sociated chemical change. In general, coprocessing ensures that deformation
can occur along any plane and multiple new surfaces are formed during the
compaction process that combines the advantages of both wet granulation and
direct compression.
185
Coprocessing is generally conducted with a combination of a plastic and a brit-
tle excipient. Maarschalk reported coprocessing with a large amount of brittle
material and a small amount of plastic material.
200
This particular combination
prevents elastic recovery during compression, which results in a smaller amount
of stress relaxation and a reduced tendency of capping and lamination.
64
How-
ever, examples of the other extreme also exist e.g., silicified MCC has a large
amount of MCC (plastic material) and a small amount of silicon dioxide (brittle
material). Hence, coprocessing these two kinds of materials produces a syner-
gistic effect, in terms of compressibility, by selectively overcoming their indi-
vidual disadvantages. Commercially available and some literature reported
coprocessed directly compressible excipients are reported in Table 5. These in-
clude examples of combination of diluent(s), and/or diluent(s)-binder(s).
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 types
201
(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
S. PATEL, A.M. KAUSHAL, & A.K. BANSAL
Ref.
207
208
209
210
211
212
213
214
215
216
217
Good compaction and bonding property, good
flowability, low degree of hygroscopicity, hard-
ness inde
p
endent of machine s
p
eed
Highly compressible, good mouthfeel, low cost
Directly compressible sugar
Better hardness of tablet, reduced friability better
flow, reduced sensitivity to wet granulation
Improved compaction with enhanced bonding
properties
Improved compaction and flow properties
Capable of formulating high dose small tablets
with poorly flowable actives
High compressibility, low lubricant sensitivity
Comments
Good compressibility and flow
Directly compressible powder
Spray dried directly compressible maltose powder
Trade name (Manufacturer)
TABLE 5. Commercially Available and Literature Reported Coprocessed Drug/Excipient(s)
Cellactose
®
(Meggle GmbH &
Co. KG Germany)
Di-Pac
®
(American Sugar, USA)
Prosolv™ (Penwest Pharmaceu-
ticals Company, USA)
Avicel
®
CE-15 (FMC Corpora-
tion, USA)
ForMaxx™ (Merck Chemicals
Ltd, UK)
Ludipress
®
(BASF AG
Ludwigshafen, Germany)
Microcelac
®
(Meggle, Germany)
Pharmatose
®
DCL40 (DMV
Veghel, The Netherlands)
StarLac™ (Roquette, France)
Advantose™ FS 95 (SPI Polyols,
Inc. USA)
Advantose™ 100 (SPI Polyols,
Inc. USA)
Method of prepa-
ration
Spray drying
Spray agglomeration
Agglomeration
Spray drying
Spray drying
Spray drying
Spray drying
Spray drying
Blending
Blending
Milling
Coprocessed
drug/excipient(s)
Lactose (93.4%),
PVP (3.2%), Crospovidone
(
3.4%
)
α-Lactose monohydrate
(
75%
)
, Cellulose
(
25%
)
Sucrose, Dextrin (3%)
MCC, Silicon dioxide
MCC, Guar gum
Calcium carbonate (70%), Sor-
bitol (30%)
α-Lactose monohydrate
(75%), Cellulose (25%)
β-lactose anhydrous (95%),
Lactitol (5%)
Lactose monohydrate (85%),
native corn starch (15%)
Fructose (95%), Starch (5%)
Maltose
46
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
Ref.
218
219
220
221
222
223
18
224
225
Comments
Good compaction and flow behavior
Direct compression antacid powder
Directly compressible xylitol
The tensile strength of composite particles is as high as spray-
dried amorphous lactose, with less elastic recovery than alpha-
lactose monoh
y
drate
Compressibility of composite particles was greater than
commercial spray-dried Eratab
®
, Cellactose
®
and Tablettose
®
Good compressibility and flow
Directly compressible adjuvant
Improved compaction than physical mixture
Compression behavior and tablet-forming ability of spray-
dried amorphous lactose was modulated by the addition of
stabilizing polymers and surfactants
Trade name (Manufacturer)
Barcroft™ Cs 90 (SPI Polyols,
Inc. USA)
Barcroft™ Premix St (SPI
Polyols, Inc. USA)
Xylitab
®
Danisco A/S, Den-
mark
—
—
—
—
—
—
Method of prepa-
ration
Spray drying
Spray drying
Spray drying
Spray-drying
Spray-drying
Wet granulation
Melt granulation
Roller compaction
Spray-drying
TABLE 5. (Continued)
Coprocessed drug/-
excipient(s)
Calcium carbonate (90%),
starch (10%)
Hydroxides of Al, Mg
and sorbitol
Xylitol, Sodium CMC
Lactose, Sodium alginate
Rice starch, MCC
MCC, Colloidal silicon
dioxide, Lactose
monohydrate, and DCP
Lactose, MCC
Powdered cellulose, Mag-
nesium carbonate
Lactose, PVP, polysor-
bate 80
Key: MCC, microcrystalline cellulose; DCP, dibasic calcium phosphate; PVP, polyvinyl pyrolidone; Na-CMC, sodium cabroxy
methylcellulose
47
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
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 strength
203
and dissolution
profile
204,205
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
MCC has excellent compressibility, whereas starch is poorly compressible and
affects tensile strength of compact. This can be addressed by substituting starch
with pregelatinized starch, which not only has better compressibility, but also
affords an improved disintegration profile. Superdisintegrants such as sodium
starch glycolate, crospovidone, and croscarmellose sodium can be used as they
act at lower concentration and are less likely to change the compaction behavior
of the blend. However, sodium starch glycolate at above 10% concentration is
known to reduce tablet tensile strength as a result of its poor compressibility.
230
Optimization of the concentration of disintegrant is thus important to avoid
their negative impact on compressibility of the tablet blend.
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 cellulose
233
as a tablet
binder in direct compression and the utility of fine-particle hydroxypropyl cellu-
lose
234
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
science-based selection of excipients. Similarly, optimization of process parame-
ters such as granulation, moisture content, and rate and magnitude of force
transfer, can help in achieving satisfactory tensile strength and desired bio-
pharmaceutical properties in tablet drug products.
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
essed diluent containing lactose and microcrystalline cellulose. Pharm Technol.
1999;22:40–6.
29. Carr RL. Evaluating flow properties of solids. Chem Eng. 1965;72:163–8.
30. Celik M. Compaction of multiparticulate oral dosage forms. In: Ghebre-Sellassie
I, editor. Multiparticulate Oral Drug Delivery. New York: Marcel Dekker; 1994.
31. Hiestand EN, Wells JE, Peot CB, Ochs JF. Physical processes of tableting. J
Pharm Sci. 1977;66:510–9.
32. David ST, Augsburger LL. Plastic flow during compression of directly com-
pressible fillers and its effect on tablet strength. J Pharm Sci. 1977;66:155–9.
33. Nystrom C, Alderborn G, Duberg M. Bonding surface area and bonding
mechanism-two important factors for the understanding of powder compac-
tability. Drug Dev Ind Pharm. 1993;19:2143–96.
34. Sun C, Grant DJ. Effects of initial particle size on the tableting properties of L-
lysine monohydrochloride dihydrate powder. Int J Pharm. 2001;215:221–8.
35. Roberts RJ, Rowe RC. Brittle-ductile transitions in sucrose and the influence of
lateral stresses during compaction. J Pharm Pharmacol. 2000;52:147–50.
36. Roberts RJ, Rowe RC. The Young's Modulus of pharmaceutical materials. Int J
Pharm. 1987;37:15–8.
37. 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 tabletting designed by spherical crystallization process.
Powder Technol. 2003;130:283–9.
38. Schmidt PC, Leitritz M. Compression force/time-profiles of microcrystalline
cellulose, dicalcium phosphate dihydrate and their binary mixtures-a critical con-
sideration of experimental parameters. Eur J Pharm Biopharm. 1997;44:303–13.
39. Nokhodchi A, Rubinstein MH, Larhrib H, Guyot JC. The effect of moisture
content on the energies involved in the compaction of ibuprofen. Int J Pharm.
1995;120:13–20.
40. Akande OF, Rubinstein MH, Rowe PH, Ford JL. Effect of compression speeds
on the compaction properties of a 1:1 paracetamol-microcrystalline cellulose
mixture prepared by single compression and by combinations of pre-
compression and main-compression. Int J Pharm. 1997;157:127–36.
41. Alpar O, Hersey JA, Shotton E. The compression properties of lactose. J Pharm
Pharmacol. 1970;22 (Suppl.):1S–7S.
42. Busignies V, Tchoreloff P, Leclerc B, Hersen C, Keller G, Couarraze G. Com-
paction of crystallographic forms of pharmaceutical granular lactoses. II.
Compacts mechanical properties. Eur J Pharm Biopharm. 2004;58:577–86.
43. Sun C. True density of microcrystalline cellulose. J Pharm Sci. 2005;94:2132–4.
44. Mattsson S, Nystrom C. Evaluation of strength-enhancing factors of a ductile
binder in direct compression of sodium bicarbonate and calcium carbonate
powders. Eur J Pharm Sci. 2000;10:53–66.
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
62. Munoz-Ruiz A, Paronen P. Time-dependent densification behavior of cyclodex-
trins. J Pharm Pharmacol. 1996;48:790–7.
63. Ebba F, Piccerelle P, Prinderre P, Opota D, Joachim J. Stress relaxation studies
of granules as a function of different lubricants. Eur J Pharm Biopharm.
2001;52:211–20.
64. Casahoursat L, Lemagen G, Larrouture D. The use of stress relaxation trials to
characterize tablet capping. Drug Dev Ind Pharm. 1988;14:2179–99.
65. Rao KP, Chawla G, Kaushal AM, Bansal AK. Impact of solid-state properties
on lubrication efficacy of magnesium stearate. Pharm Dev Technol.
2005;10:423–37.
66. Celik M, Marshal K. Use of compaction simulator in tabletting research. Drug
Dev Ind Pharm. 1989;15:759–800.
67. Doelker E, Massuelle D. Benefits of die-wall instrumentation for research and
development in tabletting. Eur J Pharm Biopharm. 2004;58:427–44.
68. Schrank-Junghani H, Bier HP, Sucker H. The measurement of die wall forces to
determine the minimum concentration of lubricant needed for tablet formula-
tions. Acta Pharm Technol. 1984;30:224–34.
69. Leitritz M, Krumme M, Schmidt PC. Force-time curves of a rotary tablet press.
Interpretation of the compressibility of a modified starch containing various
amounts of moisture. J Pharm Pharmacol. 1996;48:456–62.
70. Konkel P, Mielck JB. Associations of parameters characterizing the time course
of the tableting process on a reciprocating and on a rotary tableting machine for
high-speed production. Eur J Pharm Biopharm. 1998;45:137–48.
71. Hoblitzell JR, Rhodes CT. Determination of a relationship between force-
displacement and force-time curves. Drug Dev Ind Pharm. 1990;16:201–29.
72. Dwivedi SK, Oates RJ, Mitchell AG. Peak offset times as an indication of stress
relaxation during tableting on a rotary tablet press. J Pharm Pharmacol.
1991;43:673–8.
73. Rees JE, Hersey JA. The strength of compacts containing moisture. Pharm Acta
Helve. 1972;47:235–43.
74. Roberts RJ, Rowe RC. The effect of punch velocity on the compaction of a vari-
ety of materials. J Pharm Pharmacol. 1985;37:377–84.
75. Antikainen O, Yliruusi J. Determining the compression behavior of pharmaceu-
tical powders from the force-distance compression profile. Int J Pharm.
2003;252:253–61.
76. Ragnarsson G, Sjogren J. Work of friction and net work during compaction. J
Pharm Pharmacol. 1983;35:201–4.
77. Ragnarsson G, Sjogren J. Force-displacement measurements in tableting. J
Pharm Pharmacol. 1985;37:146–50.
78. Panelli R, Filho FA. A study of a new phenomenological compacting equation.
Powder Technol. 2001;114:255–61.
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
effect of moisture content on the rheo-mechanical properties. Chem Pharm Bull.
2003;51:751–3.
111. Li LC, Peck GE. The effect of moisture content on the compression properties
of maltodextrins. J Pharm Pharmacol. 1990;42:272–5.
112. Schepky G. Preformulation: The role of moisture in solid dosage forms. Drug
Dev Ind Pharm. 1989;15:1715–41.
113. Dawoodbahai C, Rhodes CT. The effect of moisture on powder flow and on
compaction and physical stability of tablets. Drug Dev Ind Pharm.
1989;15:1577–600.
114. Teng CD, Alkan MH, Groves MJ. The effect of adsorbed water on compaction
properties and the dissolution of quinacrine hydrochloride from compacted ma-
trices by soy protein. Drug Dev Ind Pharm. 1986;12:1325–2336.
115. Khan F, Pilpel N. The effect of particle size and moisture on the tensile strength
of microcrystalline cellulose powder. Powder Technol. 1986;48:145–50.
116. Pilpel N, Ingham S. The effect of moisture on the density, compaction and ten-
sile strength of microcrystalline cellulose. Powder Technol. 1988;54:161–4.
117. Fassihi AR. Interrelationships between yield pressure, moisture content and ten-
sile strength of microcrystalline cellulose compacts. J Pharm Pharmacol. 1988;40
(Suppl.): 76p.
118. Stubberud L, Arwidsson HG, Larsson A, Graffner C. Water solid interactions II.
Effect of moisture sorption and glass transition temperature on compactibility of
microcrystalline cellulose alone or in binary mixtures with polyvinyl pyrrolidone.
Int J Pharm. 1996;134:79–88.
119. Zografi G, Kontny MJ, Yang AYS, Brenner GS. Surface area and water vapor
sorption of macrocrystalline cellulose. Int J Pharm. 1984;18:99–116.
120. Khan F, Pilpel N. An investigation of moisture sorption in microcrystalline cel-
lulose using sorption isotherms and dielectric response. Powder Technol.
1987;50:237–41.
121. Khan KA, Musikabhumma P, Warr JP. The effect of moisture contents of
microcrystalline cellulose on the compressional properties of some formulations.
Drug Dev Ind Pharm. 1981;7:525–8.
122. Malamataris S, Karidas T. Effect of particle size and sorbed moisture on the ten-
sile strength of some tableted hydroxypropyl methylcellulose (HPMC) polymers.
Int J Pharm. 1994;104:115–23.
123. Down GRB, McMullen JN. The effect of interparticulate friction and moisture
on the crushing strength of sodium chloride compacts. Powder Technol.
1985;42:169–74.
124. Hancock BC, Carlson GT, Ladipo DD, Langdon BA, Mullarney MP. Compari-
son of the mechanical properties of the crystalline and amorphous forms of a
drug substance. Int J Pharm. 2002;241:73–85.
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
paracetamol for direct compression: the orthorhombic form. Int J Pharm.
1996;128:1–8.
156. Maggi L, Conte U, Bettinetti GP. Technological properties of crystalline and
amorphous alpha-cyclodextrin hydrates. Int J Pharm. 1998;172:211–7.
157. Sebhatu T, Elamin AA, Ahlneck C. Effect of moisture sorption on tabletting
characteristics of spray dried (15% amorphous) lactose. Pharm Res.
1994;11:1233–8.
158. Fichtner F, Rasmuson A, Alderborn G. Particle size distribution and evolution
in tablet structure during and after compaction. Int J Pharm. 2005;292:211–25.
159. Badawy SI, Lee TJ, Menning MM. Effect of drug substance particle size on the
characteristics of granulation manufactured in a high-shear mixer. AAPS
PharmSciTech. 2000;1:e33.
160. Sun C, Grant DJW. Compaction properties of L-lysine salts. Pharm Res.
2001;18:281–6.
161. Murakami H, Yoneyama T, Nakajima K, Kobayashi M. Correlation between
loose density and compactibility of granules prepared by various granulation
method. Int J Pharm. 2001;216:159–64.
162. Abberger T, Henck JO. Granule formation mechanisms in fluid-bed melt granu-
lation and their effects on tablet properties. Pharmazie. 2000;55:521–6.
163. Zuurman K, Riepma KA, Bolhuis GK, Vromans H, Lerk CF. The relationship
between bulk density and compactibility of lactose granulations. Int J Pharm.
1994;102:1–9.
164. Iloanusi NO, Schwartz JB. The effect of wax on compaction of microcrystalline
cellulose beads made by extrusion and spheronization. Drug Dev Ind Pharm.
1998;24:37–44.
165. Levina M, Rubinstein MH. The effect of ultrasonic vibration on the compaction
characteristics of ibuprofen. Drug Dev Ind Pharm. 2002;28:495–514.
166. Levina M, Rubinstein MH. The effect of ultrasonic vibration on the compaction
characteristics of paracetamol. J Pharm Sci. 2000;89:705–23.
167. Train D. An investigation into the compaction of powders. J Pharm Pharmacol.
1956;8:745–61.
168. Garr JSM, Rubinstein MH. An investigation into the capping of paracetamol at
increasing speeds of compression. Int J Pharm. 1991;72:117–22.
169. Roberts M, Ford JL, MacLeod GS, Fell JT, Smith GW, Rowe PH, Dyas AM. Ef-
fect of punch tip geometry and embossment on the punch tip adherence of a
model ibuprofen formulation. J Pharm Pharmacol. 2004;56:947–50.
170. Roberts M, Ford JL, MacLeod GS, Fell JT, Smith GW, Rowe PH. Effects of
surface roughness and chrome plating of punch tips on the sticking tendencies
of model ibuprofen formulations. J Pharm Pharmacol. 2003;55:1223–8.
171. Sugimori K, Mori S, Kawashima Y. Characterization of die wall pressure to pre-
dict capping of flat-or convex-faced drug tablets of various sizes. Powder
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
186. Wells JI, Langridge JR. Dicalcium phosphate dihydrate-microcrystalline cellulose
systems in direct compression tableting. Int J Pharm Technol & Prod Manuf.
1981;2:1–8.
187. Riepma KA, Vromans H, Zuurman K, Lerk CF. The effect of dry granulation
on the consolidation and compaction of crystalline lactose. Int J Pharm.
1993;97:29–38.
188. Wikberg M, Alderborn G. Compression characteristics of granulated materials.
VII. The effect of intragranular binder distribution on the compatibility of some
lactose granulations. Pharm Res. 1993;10:88–94.
189. Bolhuis GK. Film formation by magnesium stearate during mixing and its effect
on tableting. Pharm Weekbl. 1975;110:317–25.
190. Schmidt PC, Herzog R. Calcium phosphates in pharmaceutical tableting. 2.
Comparison of tableting properties. Pharm World Sci. 1993;15:116–22.
191. Bolhuis GK, Lerk CF. Comparative evaluation of excipients for direct compres-
sion. Pharm Weekbl. 1973;108:469–81.
192. Shangraw RF, Demarest DA. A survey of current industrial practices in the for-
mulation and manufacture of tablets and capsules. Pharm Technol. 1993;17:32–8.
193. Shangraw RF. Morphology and functionality in tablet excipients for direct com-
pression: Part II. Pharm Technol. 1981;5:44–60.
194. Guyot-Hermann AM, Leblanc D. Gamma sorbitol as a diluent in tablets. Drug
Dev Ind Pharm. 1985;11:551–64.
195. Schmidt PC. Tableting characteristics of sorbitol. Pharm Technol. 1983;7:65–74.
196. Du Ross JW. Modification of the crystalline structure of sorbitol and its effects
on tableting characteristics. Pharm Technol. 1974;8:42.
197. Debord B. Study of different crystalline forms of mannitol: comparative behav-
ior under compression. Drug Dev Ind Pharm. 1987;13:1533–46.
198. Olmo IG, Ghaly ES. Evaluation of two dextrose-based directly compressible ex-
cipients. Drug Dev Ind Pharm. 1998;24:771–8.
199. Olmo IG, Ghaly ES. Compressional characterization of two dextrose-based di-
rectly compressible excipients using an instrumented tablet press. Pharm Dev
Technol. 1999;4:221–31.
200. Maarschalk KV, Bolhius GK. Improving properties of material for direct com-
paction. Pharm Technol. 1999;23:34–46.
201. Miller TA, York P. Pharmaceutical lubricants. Int J Pharm. 1988;41:1–19.
202. Moody G, Rubinstein MH, Simmons RAF. Tablet lubricants I-Theory and
modes of action. Int J Pharm. 1981;9:75–80.
203. Zuurman K, Van der Voort Maarschalk K, Bolhuis GK. Effect of magnesium
stearate on bonding and porosity expansion of tablets produced from materials
with different consolidation properties. Int J Pharm. 1999;179:107–15.
204. Iranloye TA, Parrott EL. Effects of compression force, particle size, and
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
lubricants on dissolution rate. J Pharm Sci. 1978;67:535–9.
205. Roblot L, Duchene D, Carstensen JT. Effect of lubricant level and applied com-
pressional pressure on surface friction of tablets. J Pharm Sci. 1985;74:697–9.
206. Shah AC, Mlodozeniec AR. Mechanism of surface lubrication: influence of dura-
tion of lubricant-excipient mixing on processing characteristics of powders and
properties of compressed tablets. J Pharm Sci. 1977;66:1377–8.
207. BASF AG Ludwigshafen, Germany, Ludipress
®
product brochure.
208. Meggle GmbH & Co. KG, Germany, Cellactose
®
product brochure.
209. American Sugar, USA, Di-Pac
®
product brochure.
210. Penwest Pharmaceuticals Company, USA, Prosolv™ product brochure.
211. FMC Corporation, USA, Avicel
®
CE-15 product brochure.
212. Merck Chemicals Ltd, UK, ForMaxx™ product brochure.
213. Meggle, Germany, Microcelac
®
product brochure.
214. DMV Veghel, The Netherlands, Pharmatose
®
DCL40 product brochure.
215. Roquette, France, StarLac™ product brochure.
216. SPI Polyols, Inc., USA, Advantose™ FS 95 product brochure.
217. SPI Polyols, Inc., USA, Advantose™ 100 product brochure.
218. SPI Polyols, Inc., USA, Barcroft™ Cs 90 product brochure.
219. SPI Polyols, Inc., USA, Barcroft™ Premix St product brochure.
220. Danisco A/S, Denmark, Xylitab
®
product brochure.
221. Takeuchi H, Yasuji T, Hino T, Yamamoto H, Kawashima Y. Compaction prop-
erties of composite particles consisting of lactose with sodium alginate prepared
by spray-drying. Pharm Res. 1999;16:1193–8.
222. Limwong V, Sutanthavibul N, Kulvanich P. Spherical composite particles of rice
starch and microcrystalline cellulose: a new coprocessed excipient for direct
compression. AAPS PharmSciTech. 2004;5:e30.
223. Gohel MC, Jogani PD, Bariya SE. Development of agglomerated directly com-
pressible diluent consisting of brittle and ductile materials. Pharm Dev Technol.
2003;8:143–51.
224. Freitag F, Runge J, Kleinebudde P. Coprocessing of powdered cellulose and
magnesium carbonate: direct tableting versus tableting after roll compaction/dry
granulation. Pharm Dev Technol. 2005;10:353–62.
225. Berggren J, Frenning G, Alderborn G. Compression behavior and tablet-
forming ability of spray-dried amorphous composite particles. Eur J Pharm Sci.
2004;22:191–200.
226. Jonat S, Hasenzahl S, Gray A, Schmidt PC. Influence of compacted hydropho-
bic and hydrophilic colloidal silicon dioxide on tableting properties of pharma-
ceutical excipients. Drug Dev Ind Pharm. 2005;31:687–96.
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
227. Johansson ME. Granular magnesium stearate as a lubricant in tablet formula-
tions. Int J Pharm. 1984;21:307–15.
228. Aoshima H, Miyagisnima A, Nozawa Y, Sadzuka Y, Sonobe T. Glycerin fatty
acid esters as a new lubricant of tablets. Int J Pharm. 2005;293:25–34.
229. Jannin V, Berard V, N'Diaye A, Andres C, Pourcelot Y. Comparative study of
the lubricant performance of Compritol 888 ATO either used by blending or by
hot melt coating. Int J Pharm. 2003;262:39–45.
230. Munoz N, Ferrero C, Munoz-Ruiz A, Velasco MV, Jimenez-Castellanos MR. Ef-
fect of Explotab on the tabletability of a poorly soluble drug. Drug Dev Ind
Pharm. 1998;24:785–91.
231. Rowe RC. Correlation between predicted binder spreading coefficients and
measured granule and tablet properties in the granulation of paracetamol. Int J
Pharm. 1990;58:209–13.
232. Kolter K, Flick D. Structure and dry binding activity of different polymers, in-
cluding Kollidon VA 64. Drug Dev Ind Pharm. 2000;26:1159–65.
233. Desai RP, Neau SH, Pather SI, Johnston TP. Fine-Particle ethylcellulose as a
tablet binder in direct compression, immediate-release tablets. Drug Dev Ind
Pharm. 2001;27:633–41.
234. Skinner GW, Harcum WW, Barnum PE, Guo JH. The evaluation of fine-
particle hydroxypropyl cellulose as a roller compaction binder in pharmaceutical
applications. Drug Dev Ind Pharm. 1999;25:1121–8.
235. Mattsson S, Nystrom C. Evaluation of critical binder properties affecting the
compactibility of binary mixtures. Drug Dev Ind Pharm. 2001;27:181–94.
236. Joneja SK, Harcum WW, Skinner GW, Barnum PE, Guo JH. Investigating the
fundamental effects of binders on pharmaceutical tablet performance. Drug Dev
Ind Pharm. 1999;25:1129–35.
237. Nyström C, Mazur J, Sjögren J. Studies on direct compression of tablets. II. The
influence of the particle size of a dry binder on the mechanical strength of tab-
lets. Int J Pharm. 1982;10:209–18.
238. Al-Nasassrah MA, Podczeck F, Newton JM. The effect of an increase in chain
length on the mechanical properties of polyethylene glycols. Eur J Pharm Bio-
pharm. 1998;46:31–8.
239. Al-Angari AA, Kennerley JW, Newton JM. The compaction properties of poly-
ethylene glycols. J Pharm Pharmacol. 1985;37:151–3.
240. Mattsson S. Pharmaceutical Binders and Their Function in Directly Compressed
Tablets: Mechanistic Studies on the Effect of Dry Binders on Mechanical
Strength, Pore Structure and Disintegration of Tablets. Uppsala: Uppsala
University; 2000.
65
Electronic Data Center, http://edata-center.com Downloaded 2006-9-2 from IP 68.215.215.86 by Ajay Banga
