A Mathematical Approach To Consider Solid Compressibility in The Compression of Pharmaceutical Powders

pharmaceutics
Article
A Mathematical Approach to Consider Solid
Compressibility in the Compression of
Pharmaceutical Powders
Isabell Wünsch 1,2, * , Jan Henrik Finke 1,2 , Edgar John 3 , Michael Juhnke 3 and
Arno Kwade 1,2
1 Institute for Particle Technology, Technische Universität Braunschweig, Volkmaroder Straße 5,
Braunschweig 38104, Germany; [email protected] (J.H.F.); [email protected] (A.K.)
2 Center of Pharmaceutical Engineering (PVZ), Technische Universität Braunschweig,
Braunschweig 38106, Germany
3 Novartis Pharma AG, Basel 4002, Switzerland; [email protected] (E.J.);
[email protected] (M.J.)
* Correspondence: [email protected]; Tel.: +49-531-391-65548

Received: 12 February 2019; Accepted: 9 March 2019; Published: 15 March 2019
Abstract: In-die compression analysis is an effective method for the characterization of powder
compressibility. However, physically unreasonable apparent solid fractions above one or apparent
in-die porosities below zero are often calculated for higher compression stresses. One important
reason for this is the neglect of solid compressibility and hence the assumption of a constant solid
density. In this work, the solid compressibility of four pharmaceutical powders with different
deformation behaviour is characterized using mercury porosimetry. The derived bulk moduli are
applied for the calculation of in-die porosities. The change of in-die porosity due to the consideration
of solid compressibility is for instance up to 4% for microcrystalline cellulose at a compression
stress of 400 MPa and thus cannot be neglected for the calculation of in-die porosities. However,
solid compressibility and further uncertainties from, for example the measured solid density and
from the displacement sensors, are difficult or only partially accessible. Therefore, a mathematic term
for the calculation of physically reasonable in-die porosities is introduced. This term can be used for
the extension of common mathematical models, such as the models of Heckel and of Cooper & Eaton.
Additionally, an extended in-die compression function is introduced to precisely describe the entire
range of in-die porosity curves and to enable the successful differentiation and quantification of the
compression behaviour of the investigated pharmaceutical powders.
Keywords: powder compression; tableting; compression equations; solid compressibility; in-die

compression analysis
1. Introduction
Powder compaction is an important production process in diverse industries, such as food,
ceramic and pharmaceutical industry. The prediction of structural and mechanical properties of tablets
based on raw material properties and process parameters is still difficult or rather impossible, although
the powder compaction process was the object of numerous scientific investigations. The main
reason for the incomplete predictability is certainly the still limited process understanding due to
the complexity of the powder compaction process. This complexity can be attributed to various
influencing parameters [1–5], such as the deformation behaviour, the particle size and shape and the
compression stress on the one hand and to different acting micro-processes [6–10], such as particle
rearrangement, elastic and plastic deformation of single particles and particle fragmentation on
Pharmaceutics 2019, 11, 121; doi:10.3390/pharmaceutics11030121 www.mdpi.com/journal/pharmaceutics

Pharmaceutics 2019, 11, 121 2 of 19
the other hand. These micro-processes do not take place sequentially but occur simultaneously.
The contribution of the single mechanisms depends on material properties and applied process
parameters. Until today, the individual quantitative characterization of each mechanism is challenging.
The deformation behaviour also affects the number of generated, inter-particulate bonds as well as
the bonding forces and thus the resulting structural and mechanical properties of the tablet [11,12].
The missing predictability causes the need for a systematic and comprehensive characterization of
the compression and compaction behaviour of raw materials as prerequisite for a rationally based
formulation and process development.
This study is focused on the characterization of powder compressibility. The compressibility
is defined as the relationship between solid fraction/porosity and compression stress [8]. Several
mathematical models were developed for the description of the compression curves and the derivation
of specific compression parameters. An overview is given by Kawakita and Lüdde [13] and
Celik [14], for example. The main requirement for a suitable process function is the ability to
describe the compression curves of related materials precisely and robustly. The simplest functions are
two-parametric equations, such as the common models of Heckel [15] and of Kawakita and Lüdde [13].
These functions only depict a limited part of the compression curve. In contrast, four-parametric
models enable the description of the entire compression curve. A common four-parametric process
function is the model of Cooper & Eaton [16].
The most common method for the determination of compression curves is the out-of-die analysis
and the resulting compressibility is named out-of-die compressibility. In this case, tablets are produced
by applying different compression stresses and related tablet solid fraction/porosity is determined
after storage of the tablets at defined conditions for a period of time. However, this method is only
applicable with limitations when tablet defects, like lamination or capping, occur. Instrumented tablet
presses, equipped with force and displacement sensors, enable the determination of the compressibility
during compression (in-die compressibility). In this case, solid fraction/porosity is calculated based
on the measured force-displacement curve, taking the tablet mass and its solid density into account.
The main advantage of in-die analysis is that, in the best case, the performance of only one compression
process is sufficient for the comprehensive characterization of powder compressibility. Furthermore,
in-die compressibility can be determined even if tablet defects occur. However, in-die compressibility
is typically shifted to higher solid fractions/lower porosities compared to out-of-die compressibility,
which lead to different specific compression parameters [17–20]. The main reason for the observed
differences is the inclusion of elastic deformation in the case of in-die analysis, while out-of-die
analysis does not take elastic deformation into account as compressed powders relax during and
after unloading. Additionally, physically unreasonable apparent solid fractions above one/apparent
porosities below zero are observed for in-die analysis above certain compression stress levels [21,22].
For this reason, in-die data presented in literature are often limited to lower compression stresses
that may affect derived specific compression parameters [3,19,23]. One reason for the occurrence of
physically unreasonable values is the assumption of a constant solid density [19,21]. The molecular
lattice inside the individual particles deforms elastically during compression as well and this leads to
a decrease of specific solid volume upon compression [21,24–26]. Consequently, solid density increases
with rising compression stress, especially for organic substances. This phenomenon is referred to
as solid compressibility. As one example, Boldyreva showed for paracetamol a decrease in specific
solid volume of approximately 3% at hydrostatic compression of 400 MPa [24]. Although different
researchers mention the influence of solid compressibility as an important influencing factor on in-die
analysis, this phenomenon is scarcely considered. Sun and Grant introduced a term for the correction
of in-die porosity in dependence of the Young’s modulus of the material [17]. They showed that
the deviation between the yield strength derived by in-die analysis and out-of-die analysis increases
with decreasing Young’s modulus. Sun and Grant did not differentiate between elastic deformation
of the bulk and the single particles and solid compressibility. Additionally, Sun and Grant did not
consider the stress-dependency of solid density. The common neglect of the stress-dependency of solid
density might be explained by the inaccessibility of this phenomenon during powder compression.
The volume change of single crystals can be measured using crystallographic methods, however,
such measurements need to be performed by X-ray diffraction in sufficiently resilient dies. Another
method for the determination of solid compressibility is mercury porosimetry provided that the
single particles are completely enclosed by mercury and that all pores are completely filled with
mercury [27,28].
Further reasons for the occurrence of physically unreasonable solid fractions/porosities are
uncertainties of the compressed mass, of the measured solid density and from the force and
displacement sensors [19,29–31]. Another influencing parameter could be the die diameter, which is
assumed to be constant. However, the expansion of the die was not considered yet. These challenges are
the reason for the still more frequent use of out-of-die compressibility analysis, although in-die analysis
is material and time-saving. Katz et al. introduced a new empirical approach to use the advantages
of both methods [18,20]. They calculated out-of-die compressibility based on in-die compressibility
under consideration of elastic and viscoelastic recovery. The performance of only two compression
experiments, one at relatively low compression stress and one with maximum compression stress,
are sufficient for this approach. This method is consequently not applicable if tablet defects occur.
However, the characterization of the compression behaviour of materials which tend to form defective
tablets is important for formulation and process development. It can be concluded that a method for
the calculation of physically reasonable in-die porosities/solid fractions is needed for establishing
in-die analysis for formulation and process development.
In this study, the influence of solid compressibility and of die expansion on in-die compression
analysis is investigated for pharmaceutical materials with considerably different deformation
behaviour. Additionally, a mathematical term for the pragmatic consideration of solid compressibility
during in-die compression analysis and hence, for the calculation of physically reasonable in-die
porosities is introduced. Its applicability combined with the common compression models of Heckel
and of Cooper & Eaton, as well as an extended in-die compression function are discussed.
2. Theory
Various mathematical models for the description of powder compressibility exist in literature.
Common models in industrial pharmacy are the models of Heckel [15] and of Cooper & Eaton [16],
which are used in this study.
2.1. Model of Heckel

The model of Heckel [15] was originally developed for the compaction of metal powders with
a mainly ductile deformation behaviour. Heckel assumed that the porosity decrease during powder
compaction follows a first order kinetic:
1
ln = k·σax + A (1)
ε
where ε is the porosity, σax is the axial compression stress and k and A are constants. Heckel found that
the constant k correlates with the reciprocal value of yield strength σ0 for metals and is thus a measure
of the plasticity of a material [32]. Hersey and Rees introduced the term mean yield pressure Py for
this correlation [33]:
1 1
k= = (2)
3σ0 Py
2.2. Model of Cooper & Eaton

Cooper and Eaton describe the compression process of ceramic powders by two steps: the filling
of inter-particulate pores in the size range similar to the particle size and the filling of smaller pores [16].
They hypothesize particle rearrangement as the main deformation mechanism responsible for the first
step and plastic deformation and particle fragmentation as the main deformation mechanisms of the
second step. Cooper and Eaton consider the volume change in dependence on compression stress and
used two exponential terms for the description of both mechanisms:
V0 − V

k k
V∗ = = a1 exp − 1 + a2 exp − 2 (3)
Pharmaceutics 2019, 11, x FOR PEER V0 − V∞
REVIEW σax σax 4 of 19
where V* is the relative volume change, 𝑉 −V 𝑉 0 is the initial𝑘 volume, V ∞ is𝑘the powder volume at infinite
∗
𝑉
compression stress and a1 , a2 , k1 and = are=constants,
𝑎 𝑒𝑥𝑝 − with + the
𝑎 𝑒𝑥𝑝 − (3) of a
𝑉 k−2 𝑉 𝜎 boundary
𝜎 condition of the sum 1
and a2 equalling one. a1 and a2 are the fractions of theoretically possible compression and describe
where V* is the relative volume change, V0 is the initial volume, V∞ is the powder volume at infinite
the maximum
compressionpossible volume
stress and a1, a2, kreduction attributed to each respective mechanism. k1 and
1 and k2 are constants, with the boundary condition of the sum of ak12 are
characteristic compression
and a2 equalling values,
one. a1 and a2 arewhich indicate
the fractions of the stress range,
theoretically in which
possible the particular
compression mechanism
and describe the
dominates the volume change. In this study, the initial specific
maximum possible volume reduction attributed to each respective mechanism. volume V 0 is calculated
k1 and k2 are data
using the
of thecharacteristic
first measurement pointvalues,
compression of thewhich
force-displacement
indicate the stresscurve.
range, The specific
in which thesolid volume
particular determined
mechanism
dominates
by helium the volume
pycnometry change.
is used as In this study,
specific the initial
volume specific
at infinite volume V0 is stress
compression calculated
V ∞ .using the data
of the first measurement point of the force-displacement curve. The specific solid volume determined
by helium pycnometry is used as specific volume at infinite compression stress V∞.
3. Materials
Microcrystalline
3. Materials cellulose (MCC, Vivapur® 102, JRS Pharma, Rosenberg, Germany), anhydrous
lactose (Lac, Lactose Anhydrous NF DT, Sheffield Bio Science, Norwich, NY, USA), anhydrous
Microcrystalline cellulose (MCC, Vivapur® 102, JRS Pharma, Rosenberg, Germany), anhydrous
dicalcium phosphate (DCPA, DI-CAFOS® A150, Chemische Fabrik Budenheim, Budenheim, Germany)
lactose (Lac, Lactose Anhydrous NF DT, Sheffield Bio Science, Norwich, NY, USA), anhydrous
and paracetamol (Para, Novartis
dicalcium phosphate (DCPA, Pharma
DI-CAFOS AG, Basel, Chemische
® A150, Switzerland) wereBudenheim,
Fabrik selected as pharmaceutical
Budenheim,
materials while magnesium stearate (Faci, Carasco, Italy) was used as lubricant.
Germany) and paracetamol (Para, Novartis Pharma AG, Basel, Switzerland) were selected as
The characteristic
pharmaceutical particle
materials whilesizes of MCC,stearate
magnesium Lac and DCPA
(Faci, are Italy)
Carasco, in a comparable range but differ
was used as lubricant.
in width, The
while Para is clearly
characteristic finer
particle (Table
sizes 1). Lac
of MCC, Theandparticle
DCPAshape
are in of all model range
a comparable materials is irregular
but differ in
width,
(Figure 1). while
MCC Para is clearly
mainly finerof(Table
consists 1). Theprimary
elongated particle shape of all
particles andmodel materials is irregular
of approximately spherical
(Figure 1).orMCC
agglomerates mainly The
aggregates. consists of elongated
primary particlesprimary
of Paraparticles and of approximately
are approximately rectangular.spherical
In contrast,
agglomerates or aggregates. The primary particles of Para are
Lac and DCPA consist of irregularly shaped aggregates and agglomerates. approximately rectangular. In contrast,
Lac and DCPA consist of irregularly shaped aggregates and agglomerates.
Table 1. Characteristic particle sizes and solid density.
Table 1. Characteristic particle sizes and solid density.
x10 [µm]
MaterialMaterial x10 [µm] xx5050 [µm] x90 [µm] ρs [g/cmρ3]s [g/cm3 ]
[µm] x90 [µm]
MCC MCC 36 36 125
125 0.0080± 0.0080
261 261 1.5537 ±1.5537
Para Para 4 4 25
25 0.0001± 0.0001
72 72 1.2863 ±1.2863
Lac Lac 12 12 147
147 0.0077± 0.0077
342 342 1.5524 ±1.5524
DCPA DCPA 77 77 190
190 0.0097± 0.0097
302 302 2.7718 ±2.7718
Figure 1. Particle
Figure images
1. Particle of the
images pharmaceutical
of the pharmaceutical powders MCC,Lac,
powders MCC, Lac, DCPA
DCPA and
and Para
Para determined
determined by by
scanning electron microscopy.
scanning electron microscopy.
4. Methods
4.1. Powder Characterization

Solid density of the powders was determined using the helium pycnometer ULTRAPYC 1200
(Quantachrome Instruments, Boynton Beach, FL, USA). The powders were dried under vacuum
for 24 h before the measurement. Double measurements with 10 measurement points each were
performed and the mean values (Table 1) were used for the calculation of apparent in-die porosities.
Additionally, the true density of paracetamol was determined using the X-ray powder diffraction
(Bruker D8 Advance, Billerica, MA, USA). Three measurements were performed at room temperature
and Rietveld refinement was applied. Furthermore, particle size analysis was performed using the
laser light diffraction instrument HELOS (Sympatec, Clausthal-Zellerfeld, Germany) in combination
with the dry dispersion unit RODOS for the excipients and the wet dispersion unit CUVETTE for Para.
4.2. Determination of the Bulk Modulus

The solid compressibility of the powders was characterized using the mercury porosimeter
PoreMaster® GT60 (Quantachrome Instruments, Boynton Beach, FL, USA). The penetrometer with
a volume of 0.5 cm3 was filled with an appropriate amount of powder. The low pressure operation
(up to 344 kPa) was used for the filling of the penetrometer with mercury and is not considered for
the determination of solid compressibility because of the probably incomplete enclosure of the single
particles by mercury. The maximum applied pressure of the high pressure operation was 414 MPa.
Four samples per material were characterized and high pressure operation was repeated five times per
sample to ensure elastic deformation as the reason for volume changes. Before the analysis, several
blank measurements were performed for the consideration of the volume change due to the elastic
deformation of the penetrometer and of mercury.
The elastic compressibility of an isotropic material under hydrostatic pressure can be described
by the bulk modulus K:
dp
K = −V0 (4)
dV
where V 0 is the volume at ambient pressure and p is the hydrostatic pressure and dp can be replaced by
p−p0 and dV by V −V 0 . p0 is the atmospheric pressure and can be neglected for powder compression.
This results in
VS ( p) p
= 1− (5)
VS,0 K
where V S is the specific solid volume dependent on the hydrostatic pressure and V S,0 is the specific
solid volume at atmospheric pressure. The bulk modulus is hence the reciprocal of the slope of the
measured volume change during mercury intrusion and was determined by linear regression using
the software Excel 2010with the solver add-in (Microsoft, Redmond, WA, USA). It has to be noted that
not the whole pressure range is considered because of non-linearity at lower pressure (frequently <
150 MPa), which indicates the presence of still unfilled pores and the still insufficient enclosure of the
single particles by mercury. The bulk modulus was determined for all performed measurements and
the average value was calculated per material.
4.3. Tableting
Compaction experiments were performed using the compaction simulator Styl’One Evolution
(MEDEL’PHARM, Beynost, France), which is equipped with force and displacement sensors. The die
and the punches were manually pre-lubricated with magnesium stearate. 450 mg powder of each
MCC, Lac and Para as well as 900 mg of DCPA were compressed (n = 6) with a maximum compression
stress of 400 MPa using 11.28 mm flat-faced, round punches. The compression profile of a camshaft
was simulated with a maximum compression velocity of approximately 20 mm/s. The weight
of the tablets was measured after compaction and in-die analysis was performed considering
machine deformation. Additionally, experiments using an instrumented die (11.28 mm Euro B)

(MEDEL’PHARM, Beynost, France) were performed for the determination of the radial die wall stress
with a maximum compression stress of 300 MPa. The stress ratio, which is defined as the ratio between
radial and axial stress, is calculated based on the maximal axial and radial stresses.
The tablets were stored under constant ambient conditions for at least 24 h. Afterwards, the weight
of the tablets (n = 20) was measured and geometrical dimensions were determined using the tablet
tester MultiTest 50 FT (Dr. Schleuniger, Aesch, Switzerland). The data were used for the calculation of
out-of-die tablet porosity.
4.4. Application of the Compression Equations

The fitting of the models to experimental data was performed using regression by minimization
the sum of squared errors. The software Excel 2010 (Microsoft, Redmond, WA, USA) was used
for the fitting of the models of Heckel and of Cooper & Eaton. The fitting of the extended in-die
compression function was performed using MATLAB (Version: R2015b, MathWorks, Natick, MA,
USA). Additionally, out-of-die Heckel analysis was performed by application of the model of Heckel
to the out-of-die porosities between 200 MPa and 400 MPa.
4.5. Estimation of Radial Die Expansion

The elastic expansion of the die in radial direction during powder compression is estimated under
assumption of rotationally symmetric and height-independent stress conditions inside the die wall
based on Hook’s law [34]:
σ ν·σtan
ε rad = rad − (6)
E E
where εrad is the elastic strain in radial direction, σrad is the stress in radial direction, σtan is the elastic
stress in tangential direction, E is the Young’s modulus and ν the Poisson’s ratio. The radial stress was
measured using an instrumented die, while the tangential stress for a cylinder with a thick wall (ra /ri
≥ 1.2 according to DIN 2413) can be estimated as follows [35]:
ri2 · p r2a

σtan = 1 + (7)
r2a − ri2 r2
where ri is the inner radius, ra is the outer radius and p is the inner pressure acting on the die wall.
The estimation of die expansion was performed for Euro D compression tools with an inner radius
of 5.64 mm and an outer radius of 19.05 mm using a Young’s modulus of 210 GPa and a Poisson’s
ratio of 0.28, which are typical values of stainless steel. The influence of the die holder and the groove
are neglected.
5. Results and Discussion
5.1. Compression Behavior of the Model Materials

The in-die compression curves of the four materials differ considerably (Figure 2). The slope of the
curve of Para is the highest at the beginning of the compression process (below approximately 50 MPa)
indicating the lowest resistance against compression. In contrast, DCPA shows the overall highest
apparent in-die porosity and the lowest porosity decrease. Hence, the effective compression of DCPA
is the lowest. MCC and Lac show behaviour in between that of the aforementioned. Furthermore,
it has to be noted that physically not reasonable negative apparent in-die porosities are reached for
Para and MCC at compression stresses above 200 MPa. The reasons for the occurrence of negative
in-die porosities are discussed in the further sections.
Pharmaceutics 2019, 11, x FOR PEER REVIEW 7 of 19
Figure 2. Apparent
Figure 2. Apparent in-die
in-die compressibility
compressibility of
of MCC,
MCC, Lac,
Lac, DCPA
DCPAand
andPara.
Para.
5.2. Reasons for Apparent in-Die Porosities Below Zero

5.2. Reasons for Apparent in-Die Porosities Below Zero
A fundamental parameter for the calculation of porosities is the solid density, which is commonly
A fundamental parameter for the calculation of porosities is the solid density, which is
determined by helium pycnometry. Helium pycnometry is applicable regardless of the degree of
commonly determined by helium pycnometry. Helium pycnometry is applicable regardless of the
crystallinity in contrast to X-ray diffraction. However, variations of the solid density determined by
degree of crystallinity in contrast to X-ray diffraction. However, variations of the solid density
helium pycnometry are often reported due to the influence of material properties and measurement
determined by helium pycnometry are often reported due to the influence of material properties and
conditions [31,36,37]. The solid density of Para determined by helium pycnometry is slightly lower
measurement conditions [31,36,37]. The solid density of Para determined by helium pycnometry is
(1.2863 ± 0.001 g/cm3 ) compared to3the true density determined by X-ray diffraction (1.2936 ± 0.0027
slightly lower (1.2863 ± 0.001 g/cm ) compared to the true density determined by X-ray diffraction
g/cm3 ). The slightly lower density determined by helium pycnometry might be explained by the
(1.2936 ± 0.0027 g/cm3). The slightly lower density determined by helium pycnometry might be
consideration of closed intra-particulate pores and flaws, while these are not taken into account
explained by the consideration of closed intra-particulate pores and flaws, while these are not taken
by evaluation of X-ray diffraction. The applied high stress during powder compression causes
into account by evaluation of X-ray diffraction. The applied high stress during powder compression
particle deformation and fragmentation, which may lead to the disappearance of closed pores and
causes particle deformation and fragmentation, which may lead to the disappearance of closed pores
flaws. Therefore, the usage of the true density determined by X-ray diffraction seems to be useful
and flaws. Therefore, the usage of the true density determined by X-ray diffraction seems to be useful
for powder compression. Since often the solid density determined by helium pycnometry is used,
for powder compression. Since often the solid density determined by helium pycnometry is used, it
it is necessary to consider the influence of the differences between solid density and true density
is necessary to consider the influence of the differences between solid density and true density on the
on the calculation of in-die porosities. The lower solid density determined by helium pycnometry
calculation of in-die porosities. The lower solid density determined by helium pycnometry causes a
causes a slight shift of the apparent in-die porosity εapp,He curve of Para to slightly lower porosities
slight shift of the apparent in-die porosity εapp,He curve of Para to slightly lower porosities compared
compared to the curve calculated using the true density determined by X-ray diffraction (εapp,XRD )
to the curve calculated using the true density determined by X-ray diffraction (εapp,XRD) (Figure 3).
(Figure 3). However, in both cases physically not reasonable negative apparent in-die porosities are
However, in both cases physically not reasonable negative apparent in-die porosities are reached at
reached at high compression stresses. The apparent in-die porosities are calculated based on the
high compression stresses. The apparent in-die porosities are calculated based on the assumption of
assumption of a constant solid density during powder compression, although solid compressibility
a constant solid density during powder compression, although solid compressibility causes the
causes the increase of solid density with rising compression stress [19,21], especially for organic
increase of solid density with rising compression stress [19,21], especially for organic materials.
materials. Therefore, the bulk modulus measured by mercury porosimetry (Table 2) is used for
Therefore, the bulk modulus measured by mercury porosimetry (Table 2) is used for the calculation
the calculation of a stress-dependent specific solid volume according to Equation (5) based on the
of a stress-dependent specific solid volume according to Equation (5) based on the specific solid
specific solid volume determined by helium pycnometry. The resulting in-die compression curve εc,Hg
volume determined by helium pycnometry. The resulting in-die compression curve εc,Hg is clearly
is clearly shifted to the positive porosity range, especially at compression stresses above 200 MPa,
shifted to the positive porosity range, especially at compression stresses above 200 MPa, as Figure 3
as Figure 3 shows exemplarily for Para. The same trend is found for MCC and Lac (Table 2). The bulk
shows exemplarily for Para. The same trend is found for MCC and Lac (Table 2). The bulk modulus
modulus of the inorganic DCPA could not be determined by mercury porosimetry because of reaching
of the inorganic DCPA could not be determined by mercury porosimetry because of reaching the
the detection limit. The bulk modulus of DCPA is hence to be expected clearly higher compared
detection limit. The bulk modulus of DCPA is hence to be expected clearly higher compared to the
to the three organic materials. The bulk modulus of DCPA could be alternatively calculated using
three organic materials. The bulk modulus of DCPA could be alternatively calculated using the
the Young’s modulus and Poisson’s ratio. Beam bending of compactates or double compaction with
Young’s modulus and Poisson’s ratio. Beam bending of compactates or double compaction with a
a fully instrumented compaction simulator can be used for the determination of Young’s modulus and
fully instrumented compaction simulator can be used for the determination of Young’s modulus and
Poisson’s ratio of compactates with defined porosities [38–40]. Extrapolation to zero porosity can then
Poisson’s ratio of compactates with defined porosities [38–40]. Extrapolation to zero porosity can then
be applied for the derivation of properties of the solid, which are needed for the calculation of the bulk
be applied for the derivation of properties of the solid, which are needed for the calculation of the
modulus. Additionally, high-pressure diffraction studies of single particles could be performed [24].
bulk modulus. Additionally, high-pressure diffraction studies of single particles could be performed
[24].
Figure 3.
Figure Apparent in-die
3. Apparent in-die compressibility
compressibility of
of Para
Para calculated
calculated using
using the
the solid
solid density
density determined
determined by by
helium pycnometry
helium pycnometry εapp,He
app,He and
and by
by X-ray
X-ray diffraction
diffraction εεapp,XRD
app,XRD and
and correction
correction ofof the
the apparent
apparent in-die
in-die
compressibility εεc,Hg
compressibility with the bulk
c,Hg with bulkmodulus
modulusdetermined
determined bybymercury porosimetry.
mercury porosimetry.The The
filledfilled
areasareas
mark
the 95%
mark theconfidence interval
95% confidence regarding
interval densitydensity
regarding εapp,He εand εapp,XRD
app,He or rather
and εapp,XRD the bulk
or rather the modulus
bulk modulusεc,Hg.
εc,Hg.
Table 2. Bulk modulus determined by mercury porosimetry and minimal in-die porosities.
Table 2. Bulk modulus determined byMin.

mercury porosimetry
Apparent and minimalMin.
in-die porosity in-diein-die
porosities.
porosity
Material Bulk Modulus K [GPa]
εapp,He,min [-] εc,Hg,min [-]
Bulk Modulus K Min. Apparent in-die porosity Min. in-die porosity εc,Hg,min
Material
MCC [GPa]10.22 ± 1.02 εapp,He,min−[-]
0.035 0.006
[-]
MCC Para 14.93 ± 3.67
10.22 ± 1.02 −0.035−0.023 0.005
0.006
Lac 27.07 ± 7.13 0.001 0.016
Para 14.93 ± 3.67 −0.023 0.005
DCPA - 0.256 -
Lac 27.07 ± 7.13 0.001 0.016
DCPA - 0.256 -
The minimal in-die porosities change by approximately 3% for Para, by 4% for MCC and by
1.7%The minimal
for Lac. in-die porosities
Accordingly, change by approximately
solid compressibility 3% foreffect
has a significant Para,during
by 4% for MCCcompression
powder and by 1.7%
for
andLac. Accordingly,
should solid compressibility
be considered for the calculation has ofa significant effect during
in-die porosities. powder compression
The porosity change of DCPA and
should be considered
is expected for the calculation
to be considerably lower than of in-die
1.7%.porosities.
However,The theporosity change of
transferability of the
DCPA bulk is expected
modulus
to be considerably
determined lower than
by hydrostatic 1.7%. However,
compression the transferability
to uniaxial compression might of the bebulk modulus
limited. Thedetermined
stresses actingby
hydrostatic
on the single compression
particles during to uniaxial
uniaxial compression might be limited.
powder compression The stresses
are unknown acting on thepowder
and, additionally, single
particles
compressionduring uniaxial powder
is anisotropic compression
and dynamic, are unknown
whereas material and,bulk additionally, powder compression
moduli are generally measured at
is anisotropic
defined pressuresandanddynamic, whereas material
thermodynamic equilibrium. bulkInmoduli
addition, arethe
generally measured
stress directed at die
to the defined
wall
pressures
is complex andandthermodynamic
depends on material equilibrium. In addition,
and process the stress
parameters directed
[41,42]. to the die wall
Additionally, is complex
the accuracy of
and depends
mercury on material
porosimetry for theanddetermination
process parametersof the bulk[41,42]. Additionally,
modulus the accuracy
and uncertainties of theofmeasured
mercury
porosimetry
solid density for the determination
by helium pycnometryof hastheto bulk modulus and uncertainties of the measured solid
be considered.
densityAnby helium pycnometry
additional influencing factorhas to could
be considered.
be the elastic expansion of the die, which is dependent on
An additional
the radial influencing
stress acting on the die factor
wall.could be thestress
The radial elastic expansion
during powder of compression
the die, which is dependent
is dependent on
on
thethe radial
stress stress
ratio actingradial
between on theanddieaxial
wall.compression
The radial stress
stress,during
whichpowder
is in turn compression
determined is by
dependent
the axial
on the stress ratio
compression stressbetween
and theradial and axialincompression
used material combinationstress, with itswhich is in turnbehaviour
deformation determined by the
(Table 3).
axial compression
The stress stress
ratio in the rangeandfromthe used material in
approximately 0.5combination
MPa to 400 MPa with isitsthe deformation
highest for behaviour
MCC and
(Table 3). The stress
Para because of theratio
ductile in the
andrange from
elastic approximately
behaviour of these 0.5materials
MPa to 400 [43]MPa is theto
leading highest for MCC
the largest die
and Para because
expansion (Figureof4).
theThe ductile and
stress elastic
ratio behaviour
of Lac is in the ofmedium
these materials
range, [43]
while leading to the stress
the lowest largestratio
die
expansion
was found(Figure
for DCPA 4). (Table
The stress ratio of
3), which Lac is inwell
correlates the medium
with the range,
findingswhile the lowest stress
of Abdel-Hamid andratio
Betz was
[43].
found for DCPA
Accordingly, the (Table
expansion 3), which
of the correlates well with
die, calculated usingthe findings (6)
Equations of and
Abdel-Hamid
(7), is lowerand forBetz
Lac[43].
and
Accordingly,
DCPA. For thethe expansion
direct comparison of theofdie,
the calculated
influence of using Equationsof
the expansion (6)the
anddie(7), is lower
diameter for the
with Laceffect
and
DCPA.
of solidFor the direct comparison
compressibility, of the influence
the die expansion of the
coefficient wasexpansion
introduced of the
anddie diameter
defined with
as the the effect
reciprocal of
of
thesolid
slopecompressibility,
of the die expansion the die expansion
curves (Figurecoefficient
4). The diewas introduced
expansion and defined
coefficients as the reciprocal
are considerably larger
of thethe
than slope
bulk ofmoduli
the die(Tables
expansion 2 andcurves
3). Die(Figure 4). The
expansion die to
leads expansion coefficients
small changes of the are considerably
calculated in-die
larger than the bulk moduli (Tables 2 and 3). Die expansion leads to small changes of the calculated
in-die porosities, which are additionally recognizable by the estimated difference of porosity at

porosities, which are additionally recognizable by the estimated difference of porosity at maximum
maximum compression
compression stress of 400stress
MPa,ofcomparing
400 MPa, comparing in-diedetermined
in-die porosity porosity determined with die expansion
with die expansion to in-die
to in-die porosity determined without die expansion (Table 3). The influence of die expansion
porosity determined without die expansion (Table 3). The influence of die expansion is therefore is
therefore negligible
negligible for the calculation
for the calculation of in-die porosities.
of in-die porosities.
Table 3. Stress ratio, die expansion coefficient

coefficient and
and porosity
porosity change
change due
due to
to die
die expansion
expansion (n
(n == 6).
6).
Material
Material Stress Ratio
Stress Ratio [-]
[-] Die
DieExpansion
Expansion Coefficient
Coefficient [GPa]
[GPa] Difference
Differenceof
ofPorosity
Porosityat at400
400MPa
MPa[-]
[-]
MCC 0.47–0.81 207 ± 4 3.7 × 10−6−6
MCC 0.47–0.81 207 ± 4 3.7 × 10−6
Para 0.50–0.85 196 ± 3 4.2 × 10
Para 0.50–0.85 196 ± 3 4.2 × 10−6
Lac
Lac 0.45–0.71
0.45–0.71 237 ±
237 ± 44 2.9 × 10
2.9 ×
−6
10−6
DCPA
DCPA 0.21–0.43
0.21–0.43 382 ± 55
382 ± 1.1 ×
1.1 × 10 −6
10−6
Figure 4. Expansion of the die diameter in dependence on the applied compression stress for Para,
Figure 4. Expansion of the die diameter in dependence on the applied compression stress for Para,
MCC, Lac and DCPA.
MCC, Lac and DCPA.
Other influencing parameters for the calculation of apparent in-die porosity could be
massOther influencing
variations and the parameters
accuracy offorthe
thedisplacement
calculation ofsensors,
apparent asin-die
other porosity could be[30,31].
studies showed mass
variations
The and the determination
experimental accuracy of the of displacement sensors,
all uncertainties as other
for the studiesofshowed
calculation [30,31]. The
in-die porosities is
experimental determination of all uncertainties for the calculation of in-die
fundamentally feasible but highly expensive. However, in-die compression analysis is an advantageous porosities is
fundamentally feasible but highly expensive. However, in-die compression
method for the characterization of powder compressibility and can be applied as well for materials, analysis is an
advantageous
which tend tomethod for the characterization
form defective tablets. For thisof powder
reason, compressibility and can be applied
a pragmatic mathematical approach as well
for
for materials, which tend to form defective tablets. For this reason, a pragmatic
consideration of the physical effect of solid compressibility and other less important mechanisms mathematical
approach
is for consideration of the physical effect of solid compressibility and other less important
introduced.
mechanisms is introduced.
5.3. Introduction of the Solid Compressibility Term
5.3. Introduction of the Solid Compressibility Term
Equation (5) is valid for the volume change under hydrostatic compression. For uniaxial powder
Equationthe
compression, (5) hydrostatic
is valid for the volume
pressure canchange under hydrostatic
be approximated compression.
as follows [44]: For uniaxial powder
compression, the hydrostatic pressure can be approximated as follows [44]:
σax + 2·σ
p = 𝜎 + 2 ∙rad 𝜎 (8)
𝑝= 3 (8)
3
where σax is the stress in axial direction and σrad is the stress in radial direction. The axial and radial
where σax is the stress in axial direction and σrad is the stress in radial direction. The axial and radial
stresses acting on the single particles during uniaxial powder compression are unknown and cannot be
stresses acting on the single particles during uniaxial powder compression are unknown and cannot
measured yet due to the highly complex stress state inside the powder. In reality, a stress distribution
be measured yet due to the highly complex stress state inside the powder. In reality, a stress
exists due to the bulk structure. Usually, instrumented tablet presses enable only the measurement
distribution exists due to the bulk structure. Usually, instrumented tablet presses enable only the
of the overall axial stress acting on the powder. The overall radial stress can be determined using
measurement of the overall axial stress acting on the powder. The overall radial stress can be
an instrumented die. However, the usage of instrumented dies is not common because of difficulties
determined using an instrumented die. However, the usage of instrumented dies is not common
in design,
because of operation
difficultiesand data evaluation
in design, operation[45]. The estimation
and data evaluation of theThe
[45]. stresses actingofonthe
estimation thestresses
single
particles
acting onbased on theparticles
the single measuredbased
data is
onnot
thepossible,
measured yet,data
because of the
is not complexity
possible, of influencing
yet, because of the
complexity of influencing parameters. Therefore, the hydrostatic pressure is approximated by the
overall axial compression stress acting on the powder. Furthermore, investigations of the
parameters. Therefore, the hydrostatic pressure is approximated by the overall axial compression
stress acting on the powder. Furthermore, investigations of the compressibility of single crystals by
hydrostatic compression with high pressures up to several GPa show the decrease of specific solid
volume with rising hydrostatic pressure according to the Murnaghan equation [46]. This equation
implies a stress dependency of the bulk modulus. The stress range applied for tableting is considerably
lower compared to the applied stresses for single crystal analysis. Thus, a constant bulk modulus
is assumed within the context of this investigation. The bulk modulus K of Equation (5) is replaced
by the elastic compressibility factor C, which mainly comprises the influence of solid compressibility.
According to these assumptions Equation (5) is modified as follows:
σax
VS (σax ) = VS,0 · 1 − (9)
C
where σax is the overall axial compression stress acting on the powder and C is here referred to as
elastic compressibility factor. The in-die porosity under consideration of solid compressibility εc is
given by
Vs (σax )
ε c (σax ) = 1 − (10)
Vb (σax )
Inserting Equation (9) in Equation (10) leads to the following mathematical relation for the in-die
porosity under consideration of solid compressibility εc

VS,0 · 1 − σCax Vs,0 V ·σax V ·σax
ε c (σax ) = 1 − = 1− + S,0 = ε app (σax ) + S,0 (11)
Vb (σax ) Vb (σax ) Vb (σax )·C Vb (σax )·C
C describes mainly the elastic compressibility of the solid under uniaxial compression and is associated
with the applied determination method. Therefore, C is not a directly measured material property and
cannot be equated with the bulk modulus of single crystals. The solid compressibility term can be
included in common compression equations, such as the model of Heckel and enable the determination
of specific compression parameters under the consideration of solid compressibility.
5.4. Extension of the Model of Heckel by the Solid Compressibility Term

For the application of the solid compressibility term, the Heckel model (Equation (1)) is
transformed into its exponential form:
(− σPax − A)
ε app (σax ) = e y (12)
The limit value of the exponential term is zero and this is the necessary condition for the
determination of the elastic compressibility factor C, which is determined by fitting of Equations
(11) and (12) to the apparent in-die porosity curve from compaction experiments. Further details of the
fitting procedure are summarized in chapter 4.4.
The elastic compressibility factor C, determined by the mathematical approach, is comparable
with the bulk modulus K characterized by mercury porosimetry for Para and MCC (Table 4). The elastic
compressibility factor of Lac is somewhat lower compared to the bulk modulus, so that the influence
of solid compressibility is slightly overestimated. One possible reason for the deviation is the
mathematical method for the determination of C, which is strongly dependent on the applied models.
Additionally, the transferability of the bulk modulus determined by hydrostatic compression with
a defined pressure to uniaxial powder compression with an unknown and complex stress distribution
on the single particles might be limited. Moreover, the back-calculated elastic compressibility factor
is also influenced by other mechanisms like die expansion. For DCPA, C is considerably larger than
the values for the other three materials which correlates well with the expectation based on mercury
porosimetry. The correlation of the elastic compressibility factor with the bulk modulus is generally
good and confirms the suitability of the introduced mathematical approach for the consideration of
the effect of solid compressibility. The introduced approach provides an inexpensive method for the
correction of negative apparent in-die porosities and thus for the convergence of the apparent in-die
Pharmaceutics
porosity to 2019, 11, x in-die
the real FOR PEER REVIEW
porosity, which is not directly accessible. 11 of 19
Table
Table 4.4.Bulk
Bulkmodulus
modulus determined
determined by mercury
by mercury porosimetry
porosimetry and elastic
and elastic compressibility
compressibility factors
factors derived
derived by extension of the models of Heckel and of Cooper & Eaton with the solid compressibility
by extension of the models of Heckel and of Cooper & Eaton with the solid compressibility term and
term
by theand by the extended
extended in-die compression
in-die compression function. function.
Material Bulk Modulus K [GPa] CHeckel [GPa] CCooper &Eaton [GPa] CExtended function [GPa]
Material Bulk Modulus K [GPa] CHeckel [GPa] CCooper &Eaton [GPa] CExtended function [GPa]
MCC 10.22 ± 1.02 11.51 ± 0.17 11.87 ± 0.12 11.74 ± 0.30
MCC Para 10.22 ± 1.02± 3.67
14.93 ± 0.17
11.5115.22 ± 0.07 18.41 ±
11.87 0.12
± 0.74 15.9711.74
± 1.00 ± 0.30
Para 14.93 ± 3.67 15.22 ± 0.07 18.41 ± 0.74 15.97 ± 1.00
Lac 27.07 ± 7.13 14.09 ± 0.03 - 14.80 ± 1.46
Lac 27.07 ± 7.13 14.09 ± 0.03 - 14.80 ± 1.46
DCPA - 150.02 ± 17.24 - 277.06 ± 10.02
DCPA - 150.02 ± 17.24 - 277.06 ± 10.02
The consideration of C for the calculation of in-die porosities leads to a considerable shift of the
Heckel Theplot
consideration
to lower valuesof C for
for the
Para,calculation
MCC andofLac in-die porosities
(Figure 5). Theleads
linearto region
a considerable
and by that shiftthe
of
the Heckel plot to lower values for Para, MCC and Lac (Figure 5). The linear
applicability of the plot in general, is extended to higher compression stresses, which enables the region and by that
the applicability
application of theof the plot
Heckel modelin general,
to a more is suitable
extended fitto higher
range When compression
applying the stresses, which
correction theenables
whole
the application of the Heckel model to a more suitable fit range When applying
pressure range can be used for the evaluation of Para and MCC data. However, the curves are still the correction the
whole pressure range can be used for the evaluation of Para and MCC
bent at maximum compression stress due to the still very low porosities above approximately data. However, the curves are
stillMPa.
350 bent at
Themaximum
real in-diecompression
porosity at high stress due to the still
compression veryislow
stresses porosities
expected to beabove
slightlyapproximately
higher but is
350 MPa. The real in-die porosity at high compression stresses is expected
not experimentally accessible. Additionally, the slopes of the plots become smaller and this to be slightly higher butin
results is
not experimentally accessible. Additionally, the slopes of the plots become smaller
higher mean yield pressures (Table 5). However, the difference of Py and Py,c is very small for DCPA and this results in
higher mean
because of theyield
highpressures (Table 5). However,
elastic compressibility factor.the
Thedifference of Py and
differentiation Py,ccompression
of the is very smallbehaviour
for DCPA
because of the high elastic compressibility factor. The differentiation of the
of the different materials by Py,c is successful. The finding of the highest mean yield pressure for compression behaviour
of the different
DCPA, the lowestmaterials
for MCCby Pandy,c is a
successful.
medium value The finding
for Lac of the highestwell
correlates mean yield
with thepressure
structuralfor
DCPA, the lowest
observation (Sectionfor5.1)
MCC and
and a medium
with literaturevalue for Lac Commonly,
[23,47,48]. correlates wellthewith
yield the structural
pressure observation
is used for the
(Section 5.1) and with literature [23,47,48]. Commonly, the yield pressure is used for
classification of the plasticity of materials. It is assumed that low mean yield pressures, which indicate the classification of
athe
lowplasticity of materials.
resistance It is assumed are
against compression, thatan lowindicator
mean yield for pressures, which indicate
a high plasticity, while thea low resistance
plasticity is
against compression, are an indicator for a high plasticity, while the plasticity
decreasing with increasing mean yield pressure [47]. According to the derived mean yield pressures, is decreasing with
increasing
MCC meanpossess
and Para yield pressure
the highest[47].plasticity
According to the derived
followed mean DCPA
by Lac, while yield pressures, MCC plasticity
has the lowest and Para
possess(Table
overall the highest
5). plasticity followed by Lac, while DCPA has the lowest plasticity overall (Table 5).
(a) (b)
Figure 5.
5. (a)
(a)Heckel
Heckelplots
plotscalculated
calculatedusing
usingthe
theapparent
apparentand
andthe
thecorrected
corrected in-die
in-die porosity;
porosity; (b)
(b) corrected
corrected
Heckel plots and applied model of Heckel for Para, MCC, Lac and DCPA.
DCPA.
Table 5. Parameters derived by Heckel analysis (n = 6).
With Solid Compressibility Term

Material Py [MPa] Fit Range R2 [-] Py,T [MPa]
Py,c [MPa] Fit range
Entire Curve
MCC 72.6 ± 1.0 10–50% σmax 89.3 ± 1.2 40–90% σmax 0.9860 543.5
Para 93.5 ± 1.2 6–56% σmax 121.2 ± 2.7 30–80% σmax 0.9739 -
Lac 145.6 ± 0.5 25–75% σmax 194.5 ± 0.6 40–90% σmax 0.9935 233.1
DCPA 765.4 ± 1.5 38–88% σmax 771.2 ± 2.5 40–90% σmax 0.9313 1062.6
Table 5. Parameters derived by Heckel analysis (n = 6).
With Solid Compressibility Term

Material Py [MPa] Fit Range R2 [-] Py,T [MPa]
Py,c [MPa] Fit Range
Entire Curve
MCC 72.6 ± 1.0 10–50% σmax 89.3 ± 1.2 40–90% σmax 0.9860 543.5
Para 93.5 ± 1.2 6–56% σmax 121.2 ± 2.7 30–80% σmax 0.9739 -
Lac 145.6 ± 0.5 25–75% σmax 194.5 ± 0.6 40–90% σmax 0.9935 233.1
DCPA 765.4 ± 1.5 38–88% σmax 771.2 ± 2.5 40–90% σmax 0.9313 1062.6

It can be concluded that the quantification and differentiation of the resistance of the powder
againstItcompression
can be concluded that the
by Heckel quantification
analysis and differentiation
is successful. However, the of the resistance
Heckel of the powder
model describes only the
against
linear compression
region by Heckel
of the Heckel plot analysis
and not is successful.
the However, the
entire compression Heckel
curve. model describes
Deviations only in
are visible thethe
linear region of the Heckel plot and not the entire compression curve. Deviations are visible
low and high compression stress range, which are also the reason for the overall low goodness-of-fit, in the
low and high compression stress range, which are also the reason for the overall low goodness-of-fit,
if the whole compression curve is considered. The comprehensive differentiation of the compressibility
if the the
requires whole compression
description curve in-die
of the entire is considered.
compression Thecurves.
comprehensive differentiation
A model, which of thefor
is better suited
compressibility requires the description of the entire in-die compression curves. A model, which is
the description of the entire curve is the model of Cooper & Eaton [16].
better suited for the description of the entire curve is the model of Cooper & Eaton [16].
5.5. Extension of the Model of Cooper & Eaton by the Solid Compressibility Term
5.5. Extension of the Model of Cooper & Eaton by the Solid Compressibility Term
The criterion for the correction by the solid compressibility term (Equation (11)) when applying
The criterion for the correction by the solid compressibility term (Equation (11)) when applying
the model of Cooper & Eaton is to keep the relative volume change in the considered compression
the model of Cooper & Eaton is to keep the relative volume change in the considered compression
stress range (up to 400 MPa) lower than the limiting value of one. The model of Cooper & Eaton
stress range (up to 400 MPa) lower than the limiting value of one. The model of Cooper & Eaton
consists of two exponential terms, which are, however, able to describe relative volume changes above
consists of two exponential terms, which are, however, able to describe relative volume changes
one. Therefore, the fitting of the model including the solid compressibility term was performed using
above one. Therefore, the fitting of the model including the solid compressibility term was performed
theusing
constraint: V* ≤ 1. Thus,
the constraint: in Thus,
V* ≤ 1. the considered case, the solid
in the considered case, compressibility term is only
the solid compressibility termapplicable
is only if
theapplicable
apparentifrelative volume
the apparent change
relative converges
volume to values
change above
converges one, which
to values aboveisone,
only the case
which for the
is only MCC
and Para (Figure 6). The derived elastic compressibility factors C for Para and MCC are comparable
case for MCC and Para (Figure 6). The derived elastic compressibility factors C for Para and MCC are
to comparable
the values derived by thederived
to the values model byof Heckel andofare
the model thus and
Heckel as well in good
are thus accordance
as well in good with the bulk
accordance
with theKbulk
modulus (Table 4).
modulus K (Table 4).
1.1 1.1
1.0 1.0
Rel. volume change V * [-]
0.9
Rel. volume change V* [-]
0.9
0.8 1.05 0.8
Rel. volume change V * [-]
0.7 0.7
1.00
0.6 0.6
0.5 0.95 0.5
0.4 Para (V*c)
0.4
0.3 0.90 MCC (V*c)
0.3
Lac (V*app)
0.2 V*app V*c 0.85 0.2
Para 100 150 200 250 300 350 400 450 DCPA (V*app)
0.1 0.1
MCC Compression stress [MPa] Cooper & Eaton
0.0 0.0
0 50 100 150 200 250 300 350 400 450 0 50 100 150 200 250 300 350 400 450
Compression stress [MPa] Compression stress [MPa]
(a) (b)
Figure
Figure 6. 6.
(a)(a)Apparent
Apparentand
andcorrected
corrected relative
relative volume
volume change
changefor
forPara
Paraand
andMCC;
MCC;(b)(b)
Relative volume
Relative volume
change
change andand appliedmodel
applied modelofofCooper
Cooper& & Eaton
Eaton for Para,
Para, MCC,
MCC,Lac
Lacand
andDCPA.
DCPA.
The Thefour-parametric
four-parametricfunction
function of
of Cooper Eaton enables
Cooper & Eaton enablesthethemathematical
mathematicaldescription
description
of of
thethe
whole
whole in-die
in-die compression
compression curve.
curve. Thedeviations
The deviationsbetween
betweenexperimental
experimentaldatadataand
andthe
themodel
modelare
aresmall
smallfor
allfor
fourallpowders
four powders (Figure
(Figure 6) and
6) and thusthus the correlation
the correlation coefficients
coefficients areare high
high (Table
(Table 6).6). Obviously,
Obviously, the
the first
firstmainly
term term mainly describes
describes the volume
the volume change change
at lowatcompression
low compression stresses
stresses (<25 (< 25 MPa),
MPa), whilewhile the
the second
second
term term zero
is almost is almost
up tozero up to
10 MPa and10primarily
MPa anddescribes
primarilythe
describes
volumethe volume
change changecompression
at higher at higher
compression
stresses (Figure 7).stresses (Figure 7).
Table 6. Parameters derived by the fitting of the model of Cooper & Eaton (n = 6).
V*app With Solid Compressibility Term V*c
Material
a1[-] k1 [MPa] a2 [-] k2 [MPa] a1c[-] k1c [MPa] a2c[-] k2c [MPa] R2 [-]
MCC 0.58 ± 0.01 1.46 ± 0.16 0.45 ± 0.01 20.2 ± 1.0 0.57 ± 0.01 1.43 ± 0.20 0.45 ± 0.01 18.7 ± 0.9 0.9998
Para 0.70 ± 0.003 1.40 ± 0.10 0.35 ± 0.003 43.7 ± 2.4 0.69 ± 0.003 1.37 ± 0.10 0.34 ± 0.003 38 ± 2.0 0.9993
Table 6. Parameters derived by the fitting of the model of Cooper & Eaton (n = 6).
V* app With Solid Compressibility Term V * c

Material
a1 [-] k1 [MPa] a2 [-] k2 [MPa] a1c [-] k1c [MPa] a2c [-] k2c [MPa] R2 [-]
MCC 0.58 ± 0.01 1.46 ± 0.16 0.45 ± 0.01 20.2 ± 1.0 0.57 ± 0.01 1.43 ± 0.20 0.45 ± 0.01 18.7 ± 0.9 0.9998
Para 0.70 ± 0.003 1.40 ± 0.10 0.35 ± 0.003 43.7 ± 2.4 0.69 ± 0.003 1.37 ± 0.10 0.34 ± 0.003 38 ± 2.0 0.9993
Lac 0.52 ± 0.002 0.84 ± 0.00 0.54 ± 0.002 53.6 ± 0.4 0.9963
DCPA 0.45 ± 0.01 0.96 ± 0.10 0.42 ± 0.009 29.2 ± 1.9 0.9926
Figure 7. Individual terms of the model of Cooper & Eaton for Para.
The influence
The influence ofof the
the solid
solidcompressibility
compressibilityterm termononthe
thederived
derivedspecific
specificcompression
compression parameters
parameters is
very
is verysmall
small(Table
(Table6).6).
Only
Only k2kof Para clearly decreases. k11,,significant
2 of Para clearly decreases. k significant in
in the
the low
low compression
compression stressstress
range, is the lowest for DCPA followed by Lac, MCC and Para. The resistance
range, is the lowest for DCPA followed by Lac, MCC and Para. The resistance against filling against filling ofof large
large
pores thus increases
pores thus increases in in this
thisorder.
order.However,
However,the thedifferences
differencesbetween
between the
the four
four materials
materials areare small.
small. k2
kdiffers
2 differs more clearly. In this stress range, MCC shows the lowest resistance against
more clearly. In this stress range, MCC shows the lowest resistance against the filling of small the filling of
small pores
pores by deformation
by deformation followedfollowed by DCPA,
by DCPA, Para Para and Lac.
and Lac. The lowest
The lowest compression
compression resistance
resistance was
was expected
expected for MCC
for MCC and andthe the highest
highest for for
DCPADCPA based
based ononthetheslopes
slopesofofthe
the compression
compression curves.
curves.
Furthermore, the
Furthermore, the inapplicability
inapplicability of of the
the solid
solid compressibility
compressibility termterm for
for Lac
Lac and
and DCPA
DCPA has
has to to be
be taken
taken
into account. The differentiation of the materials based on the resistance values
into account. The differentiation of the materials based on the resistance values of the model of the model of Cooper of
& Eaton is difficult as the parameters cannot be correlated to macroscopically reasonable
Cooper & Eaton is difficult as the parameters cannot be correlated to macroscopically reasonable rank rank orders
of the materials,
orders as found as
of the materials, as well
foundbyasSonnergaard [49]. Therefore,
well by Sonnergaard [49].an extended an
Therefore, in-die compression
extended in-die
function is developed,
compression function iswhich is based
developed, on the
which is models
based on ofthe
Heckel
modelsandofofHeckel
Cooperand & Eaton.
of Cooper & Eaton.
5.6. Extended in-die Compression Function

5.6. Extended in-die Compression Function
The extended in-die compression function consists also of two exponential terms (Equation
The extended in-die compression function consists also of two exponential terms (Equation (13))
(13)) besides the solid compressibility term (Equation (11)). The counter and denominator of the
besides the solid compressibility term (Equation (11)). The counter and denominator of the exponent
exponent of the exponential terms are inverted compared with the model of Cooper & Eaton and,
of the exponential terms are inverted compared with the model of Cooper & Eaton and, by that, in
by that, in accordance to the model of Heckel. The limit value of these terms is zero, so that the solid
accordance to the model of Heckel. The limit value of these terms is zero, so that the solid
compressibility term is applicable in combination with this function.
compressibility term is applicable in combination with this function.
𝜎 σax 𝜎σax

𝜀 , c, (𝜎
ε f it )
( σ ) ε ·
ax= 𝜀 ∙ l𝑒𝑥𝑝 −
= exp − ε ·
+ 𝜀 ∙h exp − σ
+ exp − (13)
(13)
𝜎σl 𝜎h
where εl εl is the porosity change attributed to the low stress process and and σll is the bulk densification
strength which
which isissignificant
significantforforthe
thelow
lowstress process,
stress process,while εh εish the
while porosity
is the change
porosity changeattributed to the
attributed to
highhigh
the stress process
stress and σand
process h is the
σ h material
is the densification
material strength
densification of
strengththe high
of stress
the high process.
stress The sum
process. of
The
εl andofεh
sum εl equals
and εh the initial
equals theporosity at 0 MPa.
initial porosity at 0 MPa.
The in-die
The in-die porosity
porosity curves
curves areare shifted
shifted or
or rather
rather bent
bent into
into the
the positive
positive porosity
porosity range
range compared
compared
with the apparent in-die porosity curves (Figure 8), by mathematically considering
the apparent in-die porosity curves (Figure 8), by mathematically considering solid solid compressibility.
The derived in-die
compressibility. Theporosity
derivedapproaches zero for
in-die porosity materials with
approaches zerolowfor densification
materials with strength. The curves
low densification
strength. The curves of all four materials are bent to lower porosities just before reaching the
maximum compression stress. This curvature at maximum compression stress is technically caused
but does not represent the behaviour of the powder and therefore can be considered as measurement
artefact due to construction, instrumentation and operation of the compaction simulator. Based on
the small stress range in which this curvature occurs, it is not significant for the application of the
of all four materials are bent to lower porosities just before reaching the maximum compression
stress. This curvature at maximum compression stress is technically caused but does not represent the
behaviour of the powder and therefore can be considered as measurement artefact due to construction,
instrumentation and operation of the compaction simulator. Based on the small stress range in which
this curvature occurs, it is not significant for the application of the extended in-die compression
function. The deviations between in-die porosity and the function are small (Figure 8) and the
correlation coefficients (Table 7) are very high for all investigated materials. The derived elastic
compressibility factors are in good accordance with the bulk moduli for MCC and Para and are
comparable to the values derived by applying the solid compressibility term in combination with the
model of Heckel
combination with(Table 4), except
the model for DCPA.
of Heckel (TableThe 4), elastic
except compressibility
for DCPA. The factor
elasticCcompressibility
of DCPA, derived factorby
the
C ofextended in-die compression
DCPA, derived by the extended function, is considerably
in-die compression higher.isThe
function, in-die compression
considerably higher. Thecurve
in-dieof
DCPA does approximate neither the zero line nor a plateau value in the applied
compression curve of DCPA does approximate neither the zero line nor a plateau value in the applied compression stress
range. The in-die
compression stressporosities
range. The atin-die
maximum compression
porosities at maximumstresscompression
are still verystress
high (>20%). However,
are still very high
one criterion of the determination of C is the convergence of the curve to the zero
(>20%). However, one criterion of the determination of C is the convergence of the curve to the zero line. This range
is clearly
line. outside
This range (>1000outside
is clearly MPa) the considered
(> 1000 MPa) the compression
considered stress range which
compression in turn
stress range leadsintoturn
which the
mathematically
leads uncertain determination
to the mathematically of C. Furthermore,
uncertain determination a deviation between
of C. Furthermore, C andbetween
a deviation K is visible
C andfor
Lac, which was already discussed in Chapter 5.4.
K is visible for Lac, which was already discussed in Chapter 5.4.
(a) (b)
Figure 8. (a)
Figure 8. (a)Corrected
Corrected in-die
in-die porosity
porosity curves
curves and applied
and applied extended
extended compression
compression function;function; (b)
(b) Residual
Residual plot
plot for the for the
fitted fitted extended
extended compression
compression function
function for for Para,
Para, MCC, LacMCC, Lac and DCPA.
and DCPA.
Table 7. Specific compression parameters of the extended in-die compression function (n = 6).
Table 7. Specific compression parameters of the extended in-die compression function (n = 6).
Material εl [-] εl [-] σl [MPa]
Material σ l [MPa] εh [-]εh [-] σ h [MPa]
σh [MPa] C C[GPa]
[GPa] R2 R
[-]2 [-]
MCC MCC0.20 ±0.20 0.00± 0.00 8.5 ±8.5
0.6± 0.6 0.510.51
± 0.01± 0.01 79.079.0
± 1.9
± 1.9 11.74
11.74± ±
0.30
0.30 0.9998
0.9998
0.00± 0.00 4.3 ±4.3
Para Para 0.24 ±0.24 0.1± 0.1 0.280.28
± 0.00± 0.00 99.299.2 ± 3.2
± 3.2 15.97± ±
15.97 1.00
1.00 0.9993
0.9993
Lac Lac 0.14 ±0.140.01± 0.01 9.4 ±9.4
0.5± 0.5 0.320.32
± 0.00± 0.00 177.3
177.3 ± 5.6 14.80
± 5.6 14.80± ± 1.46
1.46 0.9997
0.9997
DCPA DCPA0.21 ±0.210.00± 0.0016.816.8
± 0.2± 0.2 0.470.47
± 0.00± 0.00 668.6
668.6 ± 3.5 277.06
± 3.5 277.06± ± 10.20
10.20 0.9993
0.9993
The
The first
first exponential
exponential term
term describes
describes the the low
low compression
compression stressstress range,
range, while
while the the second
second
exponential term mainly describes the high compression stress range (Figure 9).
exponential term mainly describes the high compression stress range (Figure 9). A clear distinction of A clear distinction
of
thethe bulk
bulk densification
densification strength
strength σlσof
l ofthe
thefour
fourmaterials
materialsin inthe
thelow
low compression
compression stress
stress range
range is is visible
visible
(Table 7). σσl l isis most
(Table 7). most likely
likely mainly
mainly dependent
dependent on on the
the friction
friction between
between particles
particles andand their
their Young’s
Young’s
modulus.
modulus. σσllrisesrisesininthe
the order
order Para
Para <<MCCMCC<<Lac Lac<<DCPA.
DCPA.This Thiscorrelates
correlates well
well with
with the
the experimental
experimental
findings.
findings. The
The lowest
lowest bulk
bulk densification
strength for
for Para
Para maymay bebe explained
explained by by aa facilitated
facilitated particle
particle
rearrangement due to the rectangular particle shape. σ of MCC is also low
rearrangement due to the rectangular particle shape. σl of MCC is also low because of a facilitated
l because of a facilitated
particle rearrangementdue
particle rearrangement dueto to
thethe initially
initially looseloose packing
packing (initial(initial porosity
porosity > 0.7) of> the
0.7)elongated
of the elongated
particles.
particles. Therearrangement
The particle particle rearrangement
of Lac may of Lac may be hindered
be hindered due toinitial
due to a closer a closer initial of
packing packing of the
the particles
particles because of the very broad particle size distribution. The reasons for the highest σl for DCPA
might be the hindered particle rearrangement due to a probably already very close packing of the
spherical particles and the low elasticity. These are certainly only hypothetical considerations, which
have to be proved by further investigations.
The material densification strength σh is the lowest for MCC. Para shows a slightly higher
because of the very broad particle size distribution. The reasons for the highest σl for DCPA might
be the hindered particle rearrangement due to a probably already very close packing of the spherical
particles and the low elasticity. These are certainly only hypothetical considerations, which have to be
proved by further investigations.
The material densification strength σh is the lowest for MCC. Para shows a slightly higher
resistance against compression followed by Lac. DCPA has the overall highest material densification
strength.
Pharmaceutics 2019, 11,The material
x FOR PEER densification
REVIEW strength of Para and MCC can be explained by the mainly 15 of 19
elastic and plastic deformation behaviour of these materials. The medium material densification
strength of Lac may be traced back to the higher necessary compression stress for the breakage of
deformation due to their smaller particle size. The reasons for the considerably higher material
the agglomerated/aggregated particles and the higher resistance of the primary particles against
deformation dueoftoDCPA mightparticle
their smaller be thesize.
highThe stiffness
reasonsand
for low elasticity ofhigher
the considerably this material.
material
Thedensification
extended in-die
strengthcompression
of DCPA mightfunction
be the highis well-suited forelasticity
stiffness and low the precise description
of this material. of the in-die
The extended in-die compression function is well-suited for the precise description
compression curves of all model materials and successfully mathematically considers the physical of the in-die
effect of compression curves of all model
solid compressibility. materials and
Additionally, thesuccessfully
extended mathematically
in-die compressionconsiders the physical
function enables the
effect of solid compressibility. Additionally, the extended in-die compression function enables the
successful quantification and differentiation of the compression behaviour of the materials
successful quantification and differentiation of the compression behaviour of the materials investigated.
investigated.
Figure 9. Individual terms of the extended in-die compression function for Para.
Figure 9. Individual terms of the extended in-die compression function for Para.
5.7. Comparison in- and out-of-die Compressibility
5.7. Comparison in-compressibility
Solid and out-of-dieisCompressibility
only one part of the overall elastic deformation during powder
compression. Another factor is the elastic deformation and relaxation of the framework of the
Solid compressibility is only one part of the overall elastic deformation during powder
particles, which is not considered by the introduced mathematical approach yet because of considering
compression.
only theAnother
compressionfactor
curveisbut
thenotelastic deformation
the decompression and
curve relaxation
so far. The elasticofdeformation
the framework
of the of the
particles,framework
which is isthus
nottheconsidered
main reason for bythethe introduced
differences betweenmathematical approachconsidering
the in-die compressibilities yet because of
considering only the compression
solid compressibility ε c and the curve but not the decompression
out-of-die compressibilities ε T (Figure 10). curve so far. The elastic
Therefore, the remaining
deformation of the framework is thus the main reason for the differencesthe
differences provide information on the elastic deformation of the framework within bulk. It can
between the in-die
be deduced that the elastic relaxation of the bulk framework of Lac is least pronounced while
compressibilities considering solid compressibility εc and the out-of-die compressibilities εT
the highest values are measured for MCC. It needs to be clarified whether this can be described
(Figure 10).
by anTherefore, the remaining
intercorrelation between solid differences provide
compressibility information
and deformation on the elastic
mechanisms deformation of
of the material.
the framework
Therefore,within the bulk. of
the consideration It the
candecompression
be deduced curvethat the elastic relaxation
is necessary. The out-of-dieofcompressibility
the bulk framework
of of
Lac is least
Para pronounced whilebecause
cannot be determined the highest values are
of the occurrence measured
of tablet defects duefor toMCC. It needs
capping. to be clarified
The differences
whether this can be described by an intercorrelation between solid compressibility andin-die
of the compressibility curves also cause differences of the mean yield pressures derived by deformation
Heckel analysis considering solid compressibility Py,c compared to out-of-die Heckel analysis Py,T
mechanisms of the material. Therefore, the consideration of the decompression curve is necessary.
(Table 5). Py,c is lower compared to Py,T because of the consideration of the elastic deformation of the
The out-of-die compressibility of Para cannot be determined because of the occurrence of tablet
defects due to capping. The differences of the compressibility curves also cause differences of the
mean yield pressures derived by in-die Heckel analysis considering solid compressibility Py,c
compared to out-of-die Heckel analysis Py,T (Table 5). Py,c is lower compared to Py,T because of the
consideration of the elastic deformation of the particle framework. The deformation behaviour of
particle framework. The deformation behaviour of MCC is classified as brittle based on Py,T . This is
not reasonable because of the evidently plastic deformation behaviour of MCC [23,48]. The high
mean yield pressure Py,T can be traced back to the small slope of the out-of-die compressibility
between 200 MPa and 400 MPa. Furthermore, the mean yield pressure is dependent on the
considered compression stress range. The compression behaviour of a powder is not only affected
by plastic deformation and particle fragmentation but rather by all acting micro-processes including
particle rearrangement and elastic deformation. Therefore, the comprehensive characterization of
the compression behaviour requires the consideration of the entire compression curves including the
effect of all these micro-processes. The introduced in-die approach enables such a comprehensive
characterization of powder compressibility even if tablet defects occur.
The estimation of the complete elastic recovery of the bulk solely based on in-die compression by
a further
Pharmaceutics development
2019, 11, x FOR PEERofREVIEW
the presented method using the decompression curve is a prospective aim. 16 of 19
Figure 10. Comparison of in-die porosity considering solid compressibility εc with out-of-die
Figure 10. Comparison
compressibility εT forof in-die
DCPA, porosity
Lac and MCC. considering solid compressibility εc with out-of-die
compressibility εT for DCPA, Lac and MCC.
6. Conclusions
The physical effect of solid compressibility, which causes the increase of solid density with rising
6. Conclusions
compression stress, cannot be neglected for the calculation of in-die porosities. The experimental
Thedetermination
physical effect of bulk
of the solidmodulus
compressibility,
is difficult which causes the
and expensive. increase
Therefore, of solid density
a mathematical with rising
term for
the consideration
compression stress, cannotof solid
becompressibility
neglected for is introduced based onofphysical
the calculation in-dieconsiderations.
porosities. The Thisexperimental
term
determination of the bulk modulus is difficult and expensive. Therefore, a mathematical and
can be used for the extension of common mathematical models, such as the models of Heckel term for the
of Cooper & Eaton providing an inexpensive method for the consideration of the influence of solid
consideration of solid compressibility is introduced based on physical considerations. This term can
compressibility during uniaxial powder compression. This method can be applied even if tablet
be useddefects
for theoccur.
extension of common
Additionally, mathematical
an extended models,function
in-die compression such as the models
is introduced of Heckel
based on the and of
Cooper common
& Eatonmodelsproviding
of Heckelanand
inexpensive
of Cooper & method
Eaton. Thisfor the consideration
function precisely describesof the influence
the entire in-die of solid
compression curves and enables the successful differentiation and quantification
compressibility during uniaxial powder compression. This method can be applied even if tablet of the compression
behaviour
defects occur. of the investigated
Additionally, pharmaceutical
an extended in-diepowders.
compression function is introduced based on the
The consideration of solid compressibility leads to the approach of the in-die compression curves
commontomodels of Heckel and of Cooper & Eaton. This function precisely describes the entire in-die
the out-of-die compression curves. However, differences are still visible because of the elastic
compression curves
recovery of theand
bulk,enables
which is the successfulyet.
not considered differentiation
The estimation and
of thequantification
elastic behaviourofofthethe compression
bulk
behaviour of based
solely the investigated pharmaceutical
on in-die compression powders.
by consideration of the decompression curve and thus the further
Thedevelopment
consideration of theof
presented method, is a prospective
solid compressibility leads toaim.
theContinuing,
approachthe ofsystematic
the in-die investigation
compression of curves
the influencecompression
to the out-of-die of material parameters
curves.(e.g., deformation
However, behaviour, particle
differences are stillsizevisible
and morphology)
because of up the
to elastic
complex mixtures is required to allow the evaluation of the proposed model for realistic formulations.
recovery of the bulk, which is not considered yet. The estimation of the elastic behaviour of the bulk
solely based on in-die compression by consideration of the decompression curve and thus the further
development of the presented method, is a prospective aim. Continuing, the systematic investigation
of the influence of material parameters (e.g., deformation behaviour, particle size and morphology)
up to complex mixtures is required to allow the evaluation of the proposed model for realistic
Author Contributions: Conceptualization, all authors, methodology, all authors, formal analysis, I.W.,
investigation, I.W., data curation, I.W., writing-original draft preparation, I.W., writing-review and editing,
all authors, visualization, I.W., supervision, A.K.
Funding: This research received no external funding.
Acknowledgments: We thank Dirk Märtin, Markus Matthis and Arnaud Grandeury (all Novartis Pharma AG)
and Tabea Rook, Mehmet Kale and Thorben Höltkemeier (all Technische Universität Braunschweig, Institute for
Particle Technology) for experimental support. We acknowledge financial support from the German Research
Foundation and the Open Access Funds of the Technische Universität Braunschweig.
Conflicts of Interest: The authors declare no conflict of interest. The co-authors Edgar John and Michael Juhnke
are employees of Novartis Pharma AG. Novartis Pharma AG was involved in the design, interpretation and
writing of the study, the discussion of data, revision of the manuscript, and the decision to publish the results.
Novartis Pharma had no role (effect) on the execution of the study.
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A Mathematical Approach To Consider Solid Compressibility in The Compression of Pharmaceutical Powders

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A Mathematical Approach To Consider Solid Compressibility in The Compression of Pharmaceutical Powders

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A Mathematical Approach To Consider Solid Compressibility in The Compression of Pharmaceutical Powders

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pharmaceutics

Keywords: powder compression; tableting; compression equations; solid compressibility; in-die

Pharmaceutics 2019, 11, 121; doi:10.3390/pharmaceutics11030121 www.mdpi.com/journal/pharmaceutics

2.1. Model of Heckel

2.2. Model of Cooper & Eaton

4.1. Powder Characterization

4.2. Determination of the Bulk Modulus

machine deformation. Additionally, experiments using an instrumented die (11.28 mm Euro B)

4.4. Application of the Compression Equations

4.5. Estimation of Radial Die Expansion

5. Results and Discussion

5.1. Compression Behavior of the Model Materials

5.2. Reasons for Apparent in-Die Porosities Below Zero

Table 2. Bulk modulus determined byMin.

Pharmaceutics 2019, 11, x FOR PEER REVIEW 9 of 19

Table 3. Stress ratio, die expansion coefficient

5.4. Extension of the Model of Heckel by the Solid Compressibility Term

Table 5. Parameters derived by Heckel analysis (n = 6).

With Solid Compressibility Term

Table 5. Parameters derived by Heckel analysis (n = 6).

With Solid Compressibility Term

Pharmaceutics 2019, 11, x FOR PEER REVIEW 12 of 19

V* app With Solid Compressibility Term V * c

5.6. Extended in-die Compression Function

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