PHASCI-03397; No of Pages 10

European Journal of Pharmaceutical Sciences xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

European Journal of Pharmaceutical Sciences

journal homepage: www.elsevier.com/locate/ejps

Roller compaction scale-up using roll width as scale factor and laser-based determined
ribbon porosity as critical material attribute
Morten Allesø a,b,⁎, René Holm a, Per Holm a
a
H. Lundbeck A/S, Biologics and Pharmaceutical Science, Ottiliavej 9, DK-2500, Valby, Denmark
b
NNE Pharmaplan A/S, Process Technology Consulting, Nybrovej 80, DK-2820 Gentofte, Denmark

a r t i c l e i n f o a b s t r a c t

Article history: Due to the complexity and difficulties associated with the mechanistic modeling of roller compaction process for
Received 31 August 2015 scale-up, an innovative equipment approach is to keep roll diameter fixed between scales and instead vary the
Accepted 1 November 2015 roll width. Assuming a fixed gap and roll force, this approach should create similar conditions for the nip regions
Available online xxxx
of the two compactor scales, and thus result in a scale-reproducible ribbon porosity. In the present work a non-
destructive laser-based technique was used to measure the ribbon porosity at-line with high precision and high
Keywords:
Roller compaction
accuracy as confirmed by an initial comparison to a well-established volume displacement oil intrusion method.
Ribbon porosity The ribbon porosity was found to be scale-independent when comparing the average porosity of a group of rib-
Solid fraction bon samples (n = 12) from small-scale (Mini-Pactor®) to large-scale (Macro-Pactor®). A higher standard devi-
Volume displacement ation of ribbons fragment porosities from the large-scale roller compactor was attributed to minor variations in
Direct laser measurement powder densification across the roll width.
Microcrystalline cellulose With the intention to reproduce ribbon porosity from one scale to the other, process settings of roll force and gap
size applied to the Mini-Pactor® (and identified during formulation development) were therefore directly trans-
ferrable to subsequent commercial scale production on the Macro-Pactor®. This creates a better link between for-
mulation development and tech transfer and decreases the number of batches needed to establish the parameter
settings of the commercial process.
© 2015 Elsevier B.V. All rights reserved.

1. Introduction process parameters as well as equipment design alterations; the latter

Roller compaction for dry granulation has gained increasing interest
in the pharmaceutical industry over the past decades. Improvements in
the technology such as better control over the gap, leading to more uni-
form ribbon and granule properties, and improved roller side sealing
and thus containment of fines, are key reasons for its increased popular-
ity (Kleinebudde, 2004; Miller, 2005).
Roller compaction is a continuous unit operation, meaning that a pri-
mary batch may be split into several sub-batches and processed at var-
ious combinations of process parameters. This approach carries the
potential of efficient formulation development as well as flexibility to
shift between various scales by either adjusting press roller speed
and/or gap size; however, only when their impact on granule quality
is fully understood.
Scale-up from lab/pilot to commercial scale can pose challenges that
are difficult to foresee as well as mitigate; not least because these issues
occur late in development where the formulation composition is often
fixed. This restricts scale-up control strategies to the adjustment of
⁎ Corresponding author at: NNE Pharmaplan A/S, Nybrovej 80, DK-2820 Gentofte,
Denmark.
E-mail address: MnAq@nnepharmaplan.com (M. Allesø).
typically realistic only with new equipment as a part of its installation
and qualification. Proper understanding of scale-up parameters stems
from mechanistic insight into the given process technology and its var-
ious scales. The aim of a successful scale up is therefore to create similar
process conditions for the powder material across scales through the
adjustment of process parameters. For roller compaction, assuming a
fixed granulator sieve size between pilot and commercial scale, ribbon
porosity is the most important quality descriptor of the granules' com-
pression properties and size distribution, as discussed by Allesø et al.
(2013). The proper scale-factor for compaction pressure may be found
through empirical testing at the larger scale or through the application
of powder mechanics theory (Johanson, 1965) combined with experi-
mental data (Reynolds et al., 2010; Rowe et al., 2013). Mechanics theory
can be applied to determine the nip angle/in the compaction zone when
switching to larger roll diameters. In roller compaction, the nip angle in-
dicates the compaction zone from start to end of densification, which
therefore dictates the total pressure applied to the powder (at a given
roll force) and ultimately impacts ribbon porosity. There are studies
demonstrating the use of instrumented roller compactors to acquire
the pressure profile of the powder material in the nip region
(Bindhumadhavan et al., 2005; Miguélez-Moran et al., 2008; Nesarikar
et al., 2012) as well as a recent example of roller compaction modeling

http://dx.doi.org/10.1016/j.ejps.2015.11.001
0928-0987/© 2015 Elsevier B.V. All rights reserved.

Please cite this article as: Allesø, M., et al., Roller compaction scale-up using roll width as scale factor and laser-based determined ribbon porosity
as critical material attrib..., European Journal of Pharmaceutical Sciences (2015), http://dx.doi.org/10.1016/j.ejps.2015.11.001
2 M. Allesø et al. / European Journal of Pharmaceutical Sciences xxx (2015) xxx–xxx
by computational FEM combined with experimental data (Cunningham
et al., 2010). As an alternative to first-principle understanding, Liu et al.
(2011) modeled historic data from a small-scale roller compactor by
Joint-Y PLS regression and applied it to predict the scale factor for roll
pressure on a larger scale compactor, having a larger roll diameter.
Parts of the scale-up challenges in roller compaction may also be
averted through innovative designing of the different equipment scales.
The flagship models of Gerteis® compactors include the Mini-Pactor®
and the Macro-Pactor®. A scale-comparable front-view of the two com-
pactors is shown in Fig. 1. The Mini-Pactor® is the R&D and pilot-scale
machine although the continuous nature of this unit operation makes
it suitable for production scale also depending on the processing time.
The Macro-Pactor® is Gerteis®' production scale compactor. It is very
similar to the Mini-Pactor®, the two most notable differences being
four times wider press rollers (25 mm vs. 100 mm) and a feeding
system with two tamp augers instead of one in addition to the single
feed auger that both machines have. The fact that rollers have identical
diameters between the two scales ensures an identical nip area and thus
a similar impact of roll pressure and gap size on the conveyed powder
material. Consequently, one may claim ribbon porosity to be scale inde-
pendent for these particular roller compactor types. To the best of our
knowledge there are no published studies demonstrating this.
Determination of ribbon porosity is not as trivial to determine as for
a tablet. A tablet has well defined dimensions and, using punch draw-
ings, for example, the volume of the tablet can be calculated at a specific
tablet thickness. When the tablet mass and the density of the particles
are known, the porosity can easily be acquired. Ribbons on the other
hand are irregular in shape and a frequently used method to determine
the volume of the inter-particular voids is a volume displacement meth-
od where a medium of known density is absorbed into the pores of the
sample. A long-established technique in this category is mercury
porosimetry, its major drawback being the toxicity of the mercury.
Environmentally friendly alternatives are intrusion with low viscosity
oil (Allesø et al., 2013; Khorasani et al., 2015) or a fine-particulate
solid material such as the Dry Flo® medium used for the GeoPyc®
(www.micromeretics.com).
Nkansah et al. (2008) have described a simple throughput approach
to solid fraction1 determination. Ribbons are collected in real-time with-
in a certain process time frame and weighed. The volume of ribbon
material produced in that time frame is calculated from the process
parameters gap and roll speed as well as a correction for viscoelastic
expansion. The mass and volume (per time unit) divided provide the
at-gap ribbon density. An obvious drawback of this technique is the
large sample size required for accurate porosity determination. The di-
mensional method is perhaps the most simple of all, where the volume
of the ribbon is determined by cutting the ribbon to a rectangular shape
with a trimming knife. This method, however, has a very limited use
since fragile and small ribbons, which often are the case when API is
present in the formulation, cannot be cut properly. Furthermore the di-
mensional approach does not take into account thickness variations of
ribbons manufactured using knurled or serrated rollers. Spectroscopic
techniques have also been described in the literature, though they do
not directly measure the density of the compact but rather a property
correlated with the density. These methods include near-infrared
(NIR) spectroscopy (Lim et al., 2011; Acevedo et al., 2012; Khorasani
et al., 2015; Souihi et al., 2015), where the impact of light scattering
on the baseline is considered. Recently terahertz (THz) spectroscopy
has been described, which measures the effective refractive index of
the ribbon that can be correlated to the density (Sullivan et al., 2015).
The use of a laser-based direct volume measurement device is a re-
cently introduced technique for determination of ribbon porosity (Iyer
et al., 2014a,b). The large number of ribbons needed for scale-up inves-
tigations, call for a method that efficiently analyzes ribbon porosity at a
1
Porosity = (1 − solid fraction) ∗ 100%
Please cite this article as: Allesø, M., et al., Roller compaction scale-up using roll width as scale factor and laser-based determined ribbon porosity
as critical material attrib..., European Journal of Pharmaceutical Sciences (2015), http://dx.doi.org/10.1016/j.ejps.2015.11.001
higher speed than the previously described, well-established volume
displacement approaches. The laser technique provides a result in ap-
proximately 2 min per ribbon, avoids the use of any consumable sup-
plies and is simple to utilize. Although the technique is commercially
available, literature demonstrating its performance is still sparse. There-
fore, one aim of this study was to compare the laser-based porosity
method against a volume displacement method using low viscosity oil
(medium chain triglyceride, MCT). Another aim of the present study
was to investigate the hypothesized scale independence of ribbon po-
rosity, when roller compaction scale-up was done by means of a roll
width increase from 25 mm to 100 mm on Gerteis® compactors.
2. Materials and methods
2.1. Materials
Microcrystalline cellulose (Avicel PH102) and croscarmellose sodium
(Ac-Di-Sol) were sourced from FMC Health and Nutrition (Philadelphia,
PA, USA) and used as filler/binder and superdisintegrant, respectively.
Magnesium stearate (Peter Greven GmbH & Co.KG, Bad Münstereifel,
Germany) was added as lubricant to reduce friction between the powder
and metal surfaces of the roller compactor. Medium chain triglyceride
was obtained from Delios V (Illertissen, Germany).
2.2. Experimental design
All samples consisted of microcrystalline cellulose (diluent) and
0.75% magnesium stearate. A two-factor, two level design was carried
out at each roller compactor equipment scale, with the factor gap size
at levels 2.0 and 4.0 mm and the factor, roll force at levels 3.0 and 11.0
kN/cm. The study included a center point with a gap of 3.0 mm and
roll force of 7.0 kN/cm. For the comparison of the two porosity measure-
ment techniques (laser and oil; see below), a total of six ribbons were
analyzed per experiment (five in total) per equipment scale (two), i.e.
6 × 5 × 2 = 60 ribbons in total. Every ribbon was first analyzed by the
non-destructive laser method and finally subjected to the destructive
oil intrusion method.
For comparison of roller compactor equipment scales, the sample
population was increased from six to n = 12, the additional six ribbons
only being analyzed by the laser method.
An additional four experiments were conducted separately with the
intention to sample an entire 100 mm ribbon from the Macro-Pactor®
(see below) and assess the within-ribbon porosity variability. Four com-
binations of gap and roll force where investigated, but this time at rela-
tively high roll pressures, since whole ribbons are difficult to sample
when they get too fragile. The investigated settings were 2.0 and
4.0 mm gap and 7.0 and 11.0 kN/cm.
2.3. Roller compaction
The microcrystalline cellulose was mixed with magnesium
stearate in a Bohle LM40 bin blender of suitable size (L.B. Bohle,
Ennigerloh, Germany). Dry granulation was carried out on the small-
er scale Mini-Pactor® (Gerteis® Maschinen + Processengineering
AG, Jona, Switzerland) equipped with 25 mm wide rolls as well as
on its larger scale equivalent, the Macro-Pactor®, equipped with
100 mm wide rolls. Gap size and roll force were varied according to
the design described in the previous section. Roll speed was
6.0 rpm and the feed/tamp auger ratio was 250%. Auger speed was
automatically adjusted by the gap control feature in order to ensure
a stable gap during processing. A stable gap was confirmed for all in-
dividual experiments of this study. Sample collection (see below)
was performed once the roller compactor had reached its target set-
ting for gap and roll force.
 M. Allesø et al. / European Journal of Pharmaceutical Sciences xxx (2015) xxx–xxx 3

Fig. 1. Scale-comparable front view of Gerteis®’ A) Mini-Pactor® and B) Macro-Pactor® roller compactors. The rolls, and thus produced ribbons, are four times wider for the Macro-
Pactor® as shown in the bottom of the picture.

2.4. Sample collection during roller compaction 2.5. Ribbon porosity determination

2.4.1. Mini-Pactor® (small scale) 2.5.1. Laser-based technique

The process was run without granulator to avoid clogging of the
space between the rolls and the granulator region and to minimize
wear on the screen mesh. This was particularly relevant in the experi-
ments where hard ribbons (i.e. low porosity) were produced. Samples
of ribbons from the Mini-Pactor® were collected in real-time from a
sample collection port, located underneath the rollers and the left-side
scraper. Of the collected ribbons from all five batches, most were al-
ready of a size suitable for porosity measurement by the laser and oil in-
trusion method (see below).
The porosity of the ribbons was measured using a laser-based direct
volume measurement device (Solid Fraction Measurement Systems,
Centerbrook, CT, USA). The approach uses two laser displacement sen-
sors capable of measuring the distances to the top and bottom of the rib-
bon. Since the distance between the two lasers is known, it is possible to
compute the thickness of the object being measured at the point of mea-
surement. The various distances relevant to the thickness measurement
are illustrated in Fig. 2.
Given this relationship, the thickness of the sample (T) at the laser
beam is given by:

2.4.2. Macro-Pactor® (large scale) T ¼ D−U−L

Even after scraping off the left side roller, the ribbons were still too
large to sample while the equipment was running. Since representative
sampling is best ensured through sampling in real-time, it was decided
to configure the granulator with an open star rotor, however, operating
it without any screen support. That way the granulator broke the large
100 mm ribbons into smaller ribbon fragments that could be sampled
in real-time from the granulator outlet. Most of these fragments were
of suitable size for the following porosity measurements by the laser
and oil intrusion method (see below).
The four experiments in the intra-ribbon variability study required
sampling of an entire ribbon. To achieve this, the process was allowed
to run to steady-state (i.e. target settings of gap and roll force) and
thereafter brought to immediate stop. A 100 mm wide ribbon attached
to the left-side roller was manually removed and kept for later fragmen-
tation with a trimming knife and porosity determination by the laser
method.
where U and L are the distances measured by the Upper and Lower la-
sers to the top and the bottom of the sample, respectively, and D is
the known distance between the lasers.
By making measurements of the thickness of the sample at a large
number of points on the surface of the sample, and then integrating
this thickness data, one can determine the volume of the sample being
tested. In practice, the ribbon is held by a set of jaws attached to a com-
puter controlled precision XYZ stage, the XY direction controlling the
movement during scanning of a ribbon.
After the volume measurements are complete, the ribbon is trans-
ferred (automatically) to a precision weighing module within the
laser-based system, where its mass (mribbon) is determined. Given the
mass of the ribbon and the volume of the sample, the density (ρribbon)
of the sample can be computed as ρribbon = mribbon/Vribbon.

Please cite this article as: Allesø, M., et al., Roller compaction scale-up using roll width as scale factor and laser-based determined ribbon porosity
as critical material attrib..., European Journal of Pharmaceutical Sciences (2015), http://dx.doi.org/10.1016/j.ejps.2015.11.001
4 M. Allesø et al. / European Journal of Pharmaceutical Sciences xxx (2015) xxx–xxx
Fig. 2. Illustration of the basic principle of the laser-based ribbon volume measurement.
Given the operator's input of the density of the particles (ρp), which
were compressed to form the ribbon, the ribbon porosity (εribbon) can be
computed as:
!
ρribbon
ε ribbon ¼ 1−  100%:
ρp
The reader is referred to the work by Iyer et al. (2014a,b) for a more
detailed description of the system.
In the current study, a scan step size of 0.7 mm in the Y-direction
(resolution) was applied to almost all ribbon measurements, providing
a total analysis time (from ribbon loading to display of result) of less
than 2 min. In the Macro-Pactor® intra-ribbon variability study (see
the Experimental Design section), a few ribbon fragments, regarded as
exceptionally small in size, were scanned at a 0.4 mm step size. The
scan step size in the X-direction was fixed at 0.01 mm. The value for
ρp (true density) of the MCC and magnesium stearate mixture used in
the current study was 1.565 g/cm3 and was determined using an
AccuPyc 1330 (Micromeritics, Norcross, GA, USA).
2.5.2. Oil intrusion method
The sample ribbon (with known weight) was kept under vacuum
(approximately 1 mBar) in a desiccator and immersed in a low viscosity
Please cite this article as: Allesø, M., et al., Roller compaction scale-up using roll width as scale factor and laser-based determined ribbon porosity
as critical material attrib..., European Journal of Pharmaceutical Sciences (2015), http://dx.doi.org/10.1016/j.ejps.2015.11.001
oil. The vacuum was then released and the sample was allowed to ab-
sorb oil into the internal ribbon pores for 2 h. Excess oil was removed
by wiping the ribbons carefully with a tissue. The amount of oil
absorbed (moil) was calculated by measuring the increase in mass of
the sample. Given that the density of the oil (ρoil) and the density of
the particles (ρp) were known, the volume of the oil (Voil) and the vol-
ume of the particles (Vp) could be calculated as basis for the calculation
of ribbon porosity (εribbon):
 
V oil
εribbon ¼  100%
V oil þ V p
where Voil = moil/ρoil and Vp = mribbon/ρp.
Medium chain triglyceride oil was used in this study and its density
at room temperature is 0.942 g/cm3
2.6. Statistical analysis
Statistical comparison of the medians from two groups of samples
(Mini-Pactor® vs Macro-Pactor®) was performed by the Mann–Whitney
U test using SigmaPlot (ver. 11.2.0.5, Systat Software, Inc., San Jose CA,
USA). The results were considered significant if P b 0.05
3. Results and discussion
3.1. Performance of the laser method for ribbon porosity determination
Ribbon porosities measured by the laser and oil intrusion method
are listed in Tables 1 and 2, reflecting samples processed on the small-
scale Mini-Pactor® and large-scale Macro-Pactor®, respectively. Due
to varying combinations of roll force and gap size, the five batches
span a relatively broad range of ribbon porosities, batch #1 including
the most fragile ribbons with the highest porosity (approximately
50%), while the hardest ribbons (approximately 20% porosity) were
found in batch #3. Overall the laser and oil intrusion method provided
very similar results and both corroborated the effect of gap size and
roll force on ribbon porosity that one would expect. Increasing the roll
force from 3.0 to 11.0 kN/cm, at a fixed gap of 4.0 mm, increased the
powder densification and consequently reduced ribbon porosity from
51.1% (laser) to 25.2% (laser) on the Mini-Pactor® (Table 1), with com-
parable numbers on the Macro-Pactor® being 50.6% and 26.0%, respec-
tively. At a fixed gap of 2.0 mm, a similar increase in roll force decreased
the laser-determined ribbon porosity from 47.1% to 21.2% (Mini-
Pactor®), and 44.5% to 21.6% (Macro-Pactor®), i.e. approximately the
same absolute loss in porosity irrespective of gap size suggesting that
gap size and force do not interact for this placebo formulation. The effect
of gap size was positively correlated to the ribbon porosity, although
much less pronounced than the effect of force. Here an increased gap
size from 2.0 to 4.0 mm increased the porosity by approximately 6% at
both a 3.0 kN/cm roll force (batches #2 and #1) and at 11.0 kN/cm
roll force (batches #3 and #4). This negative effect of roll force on ribbon
porosity is logical and follows the same principles of powder densifica-
tion as for any compaction process, e.g. tablet compression. While stud-
ies investigating the effect of gap can be found, they are less common
than those related to roll force since many studies operate the roller
compactor at a fixed gap. Rambali et al. (2001) conducted dry granula-
tion trials on a compactor with movable gap and inclined roll configura-
tion, i.e. similar to the type used in this study, and found that an increase
in gap from 2.0 to 3.0 mm slightly, yet significantly, increases the tensile
strength of the resulting tablets compressed from the roller compactor
(RC) granules. Although they did not assess the ribbon density, the
higher tablet strength suggests better recompactability of the MCC-
based granules, which ultimately is linked to higher ribbon porosity,
and thus a higher number of inter-particulate bonding sites available
for subsequent tablet compression. Bindhumadhavan et al. (2005) in-
vestigated the effect of gap size using an instrumented roller compactor
 M. Allesø et al. / European Journal of Pharmaceutical Sciences xxx (2015) xxx–xxx 5

Table 1
Mini-Pactor® ribbon porosity results from the oil-based method and laser method. Each ribbon was first measured by the non-destructive laser-based system, then followed by an oil
intrusion measurement, the latter being destructive.

Mini-Pactor®

Batch # Technique Ribbon porosity, % (six ribbons) Avg. St.dev. ΔPorosity

(%) (%) (oil-laser)
1 2 3 4 5 6

#1 Oil 51.1 49.9 50.8 51.8 51.1 51.4 51.0 0.6 −1.0%
Gap: 4.0 mm Laser 50.5 51.8 52.2 52.4 52.5 52.4 52.0 0.8
Force: 3.0 kN/cm
#2 Oil 44.5 44.8 44.4 44.5 45.8 45.7 45.0 0.6 −2.1%
Gap: 2.0 mm Laser 46.2 46.7 47.7 46.3 48.0 47.5 47.1 0.8
Force: 3.0 kN/cm
#3 Oil 18.9 18.5 18.1 18.0 18.5 19.0 18.5 0.4 −2.7%
Gap: 2.0 mm Laser 21.3 21.0 21.4 21.0 21.1 21.4 21.2 0.2
Force: 11.0 kN/cm
#4 Oil 25.3 25.1 24.9 25.2 25.4 25.2 25.2 0.2 −2.0%
Gap: 4.0 mm Laser 27.2 27.7 26.8 26.8 27.1 27.5 27.2 0.4
Force: 11.0 kN/cm
#5 (CP) Oil 33.1 31.8 32.3 32.9 31.8 32.7 32.4 0.6 −2.0%
Gap: 3.0 mm Laser 35.9 33.9 34.1 34.4 33.6 34.9 34.5 0.8
Force: 7.0 kN/cm

and found that the average maximum pressure between the rolls de-
creases at higher roll gap, eventually leading to more porous ribbons.
The ribbon porosities shown in Tables 1 and 2 are depicted graphically
in Fig. 3. The linear correlation between the laser- and the oil-based poros-
ity data was excellent (R2 = 0.99) for both the Mini- and Macro-Pactor®
datasets. For the six samples from each batch manufactured on the Mini-
Pactor®, both porosity measurement techniques provided very low
standard deviations (SD's), where the laser SD was slightly less than
0.8% and the oil-based SD was slightly less than 0.6%. The porosity distri-
bution of the six samples collected from the large scale Macro-Pactor®
was broader, with SDs from 1.9% to 3.0% and 1.6% to 3.1% for the laser
and oil-based methods, respectively. The excellent correlation between
the two methods for the Macro-Pactor® (same ribbons analyzed), irre-
spective of the porosity variability within a batch, confirmed that the
higher SDs were in fact attributed to the roller compaction process and
not a lack of accuracy of the porosity determinations. This impact of
scale on the porosity distribution is further investigated in the following
section.
Although the two porosity determinations performed equally well in
their ability to detect systematic and random porosity variations en-
countered during processing, the positive offset of the regression line
of 3.6% and 3.2% for the Mini- and Macro-Pactor® suggests a tendency
of the oil intrusion method to underestimate the porosity relative to
the laser method. The average value (n = 6) of the laser-based
porosities subtracted from the oil intrusion porosities are depicted in
Fig. 4 as quartiles (n = 6) in a box plot against the average ribbon poros-
ity determined by the laser method. For the 25 mm ribbons (Mini-
Pactor®), the biggest underestimation of the oil-based method was
found for the strongest ribbons of low average porosity (21.2%, batch
#3). These samples were underestimated by as much as 3%, whereas
the samples in-between approximately 27 and 47% porosity (average
values) were generally underestimated by 2% (batches #2, #4 and
#5). In contrast, for the most fragile ribbons (51.5% porosity, batch
#1) the differences in porosities were close to 0% confirming better
agreement between the two techniques than with the other ribbon
batches. A similar pattern of underestimations was identified in the
Macro-Pactor® dataset, although the lowest porosity ribbons (21.6%)
were underestimated by approximately 2%, which was in the same re-
gion as for the ribbon batches of 28 and 45% porosity (average values).
It can be argued as to whether the discrepancy between the two
methods represents an underestimation of the oil intrusion method or
an overestimation by the laser method. However, the nature of the vol-
ume displacement method supports the hypothesis that this method is
underestimating the results slightly. Both the lasers and the balance of
the laser system were calibrated against certified standards, and the vol-
ume and mass provided can therefore be assumed to be highly accurate.
Volume displacement methods, such as the one used in the present
study, rely on the complete absorption of the liquid medium into the

Table 2
Macro-Pactor® ribbon porosity results from the oil-based method and laser method. Each ribbon was first measured by the non-destructive laser-based system, then followed by an oil
intrusion measurement, the latter being destructive.

Macro-Pactor®

Batch # Technique Ribbon porosity, % (six ribbons) Avg. St. dev. ΔPorosity
(%) (%) (oil-laser)
1 2 3 4 5 6

#1 Oil 50.3 49.2 49.9 49.8 50.0 53.7 50.5 1.6 −0.1%
Gap: 4.0 mm Laser 50.8 49.9 48.2 49.4 51.5 53.9 50.6 2.0
Force: 3.0 kN/cm
#2 Oil 44.9 45.5 39 40.7 43.8 43.6 42.9 2.5 −1.6%
Gap: 2.0 mm Laser 46.0 46.8 41.3 42.3 45.6 44.9 44.5 2.2
Force: 3.0 kN/cm
#3 Oil 19.0 16.2 21.1 22.4 17.7 21.1 19.6 2.4 −2.0%
Gap: 2.0 mm Laser 22.2 18.3 22.9 22.8 20.4 23.1 21.6 1.9
Force: 11.0 kN/cm
#4 Oil 22.5 25.5 28.1 23.5 27.5 28.9 26.0 2.6 −1.5%
Gap: 4.0 mm Laser 24.0 27.7 28.8 24.7 29.3 30.5 27.5 2.6
Force: 11.0 kN/cm
#5 (CP) Oil 36.7 35.2 33.5 29.7 29.6 29.9 32.4 3.1 −2.1%
Gap: 3.0 mm Laser 38.5 38 34.4 32.0 32.2 32.0 34.5 3.0
Force: 7.0 kN/cm

Please cite this article as: Allesø, M., et al., Roller compaction scale-up using roll width as scale factor and laser-based determined ribbon porosity
as critical material attrib..., European Journal of Pharmaceutical Sciences (2015), http://dx.doi.org/10.1016/j.ejps.2015.11.001
6 M. Allesø et al. / European Journal of Pharmaceutical Sciences xxx (2015) xxx–xxx
Fig. 3. Plot of ribbon porosities determined by oil intrusion against the laser-based results
for (A) Mini-Pactor® ribbons and (B) Macro-Pactor® ribbons. Each sample coordinate in
the plot represents the same ribbon analyzed first by the laser system and then by oil
intrusion.
pores of the compact, and the liquid will not be able to enter closed
pores of the compact. Incomplete intrusion would result in an underes-
timation of the pore volume and thus porosity, a probability that is log-
ically expected to be higher for hard compacts and lower for fragile
compacts. The experimental results plotted in Fig. 4 support this
explanation.
Finally, the non-destructive nature of the laser method enabled the
assessment of repeatability, an analytical parameter that cannot be ac-
quired for the oil intrusion method. Three single ribbons, from batches
which represented the edges of the experimental space (batches #1
and #3) and the center point (batch #5), were selected for repeatability
analysis. Each of these ribbons was measured six consecutive times with
the laser system. The porosity results, including the raw data volume
and mass, are presented in Table 3. With a standard deviation of merely
0.2% across the entire porosity range from 21 to 53%, the laser system
clearly performs consistently with a high precision. Interestingly, the
raw data reveal a very minor wear of the ribbons during the repeated
performance of the six measurements. This was seen as a reduction in
the initial mass from start to end by approximately 6 mg for the fragile
ribbons and 2 mg for the strong ribbons. This wear was mainly a conse-
quence of the jaws grasping the ribbon, as this was the only stress ap-
plied to the ribbons. This, however, does not impact the validity of the
results since the ribbon volume correspondingly was measured to be
lower by the lasers.
Please cite this article as: Allesø, M., et al., Roller compaction scale-up using roll width as scale factor and laser-based determined ribbon porosity
as critical material attrib..., European Journal of Pharmaceutical Sciences (2015), http://dx.doi.org/10.1016/j.ejps.2015.11.001
Fig. 4. Box plot showing the distribution of differences between ribbon porosities deter-
mined by oil intrusion and the laser method at given mean porosity (measured by the
laser). Data are shown for A) Mini-Pactor® and B) Macro-Pactor®. A negative value indi-
cates an underestimation by the oil-based method. The bottom and top of each box are the
first (25%) and third (75%) quartiles, and the band inside is the second quartile or median
(50%). The red dashed line is the mean value (n = 6).
Collectively, the data suggested that the laser system was very suit-
able for further investigations of the Mini- and Macro-Pactor® ribbons,
hence it was the only porosity measurement technique used in the fol-
lowing scale-up investigations.
3.2. Impact of roller compaction scale on ribbon porosity
As evident from Tables 1 and 2, ribbon fragments from the Macro-
Pactor® runs yielded a higher standard deviation compared to ribbons
collected from the Mini-Pactor®. This was not unexpected since every
collected ribbon sample from the Mini-Pactor® represented the entire
25 mm roll width (see picture of ribbon in Fig. 1). In contrast, a sample
population of n = 6 ribbons from the Macro-Pactor®, although sampled
in real-time, consisted of random fragments from several 100 mm rib-
bons, which resulted in a broader porosity distribution. The variability
of 25 mm ribbons collected from the Micro-Pactor® may be considered
to be a true measure of between-ribbon variability, whilst for the
Macro-Pactor® the measurement variability represents a mixture of
within-ribbon (i.e. fragments taken from the same 100 mm primary rib-
bon) and between-ribbon variability. Hence, to improve sampling in an
attempt to obtain a better measurement of the average porosity of the
100 mm primary ribbon, the sample population was increased from
six to twelve. This increase in population size was done for both the
 M. Allesø et al. / European Journal of Pharmaceutical Sciences xxx (2015) xxx–xxx 7

Table 3
Results demonstrating the repeatability of the laser-based technique. Six repeated measurements were performed on a single ribbon selected from each of three separate.

Measurement no. Batch #1 Batch #3 Batch #5

(fragile ribbon) (intermediate ribbon) (hard ribbon)

Volume Mass Porosity Volume Mass Porosity Volume Mass Porosity

(cm3) (mg) (%) (cm3) (mg) (%) (cm3) (mg) (%)

1 528.4 391.5 52.7 1020.0 1033.2 35.3 533.4 652.9 21.8

2 523.2 390.0 52.4 1021.6 1031.8 35.5 529.5 652.2 21.3
3 527.9 389.5 52.9 1019.4 1030.7 35.4 529.0 651.9 21.3
4 526.8 388.3 52.9 1019.4 1030.0 35.4 528.1 651.7 21.2
5 522.5 385.7 52.8 1018.7 1029.4 35.4 527.9 651.2 21.2
6 522.1 385.2 52.9 1011.2 1028.9 35.0 528.8 651.0 21.3
Average 52.8 Average 35.3 Average 21.4
St. dev. 0.2 St. dev. 0.2 St. dev. 0.2

Mini-Pactor® and Macro-Pactor® samples, and again the former twelve
samples were complete 25 mm ribbons, and the latter twelve samples
were twelve fragments chosen randomly from the 100 mm primary rib-
bon. Table 4 summarizes the average porosities from the 12 measure-
ments per batch and also shows the raw data, ribbon volume and
mass, constituting the basis of the reported porosity results. The in-
crease in sample population did not improve the ribbon porosity distri-
bution of the Macro-Pactor®, but rather slightly increased the standard
deviation (now up to 3.3%). Standard deviations were generally very
low in the ribbons from the Mini-Pactor®, 1.0% or lower, with the ex-
ception of batch #1. Although not shown in Table 4, a single measure-
ment from Mini-Pactor® batch #1 was primarily responsible for the
larger SD. (11 out of 12 measurements fell within the 50.5% to 52.3% po-
rosity range, with a single outlier measurement at 45.1%. Omitting the
outlier from the dataset provides an average Mini-Pactor® ribbon po-
rosity for batch #1 (n = 11) of 51.9% and brings the SD down to 0.6%,
which was comparable to the SDs of the all other ribbon batches from
the Mini-Pactor®. It was decided, however, not to discard the outlier
measurement, since triplicate measurements on that same ribbon
gave similar porosities (45.1, 45.3, and 45.5%).
There was an excellent agreement between the average ribbon po-
rosity obtained on the Mini- and Macro-Pactor® when operating the
compactor at identical settings of roll force and gap size. A statistical
comparison of medians did not suggest any difference between the
two compactor scales for batches #1, #2, #4 and #5 at 95% confidence.
From a practical point of view the average ribbon porosities of batch #3
were very similar for the two scales, 20.8% for the Mini-Pactor® and
22.0% for the Macro-Pactor®, but due to low SDs on both scales (1.0%
and 1.7%) they became statistically different at the 95% confidence
level. The data of Table 4 are depicted graphically in Fig. 5. The excellent
linear correlation (R2 = 0.996) between ribbon porosities obtained on
the two compactor scales confirm the expected 1:1 scalability of the
Mini- and Macro-Pactor®.
To gain more insight into the variability between ribbons
manufactured on the Macro-Pactor®, four additional batches were
manufactured, with settings of force and gap providing average ribbon
porosities which ranged from approximately 28% to 37%. While in gen-
eral 100 mm ribbons break up into fragments as they leave the roller,
the relatively low porosity of these special batches allowed collection
of complete 100 mm wide ribbons. Three whole ribbons per batch
were sectioned into eight segments with a trimming knife (Fig. 6) and
the porosity of each individual segment was determined using the
laser-based method giving a total of 3 × 8 measurements per batch.
The porosity data are listed in Table 5 also showing the total measured
volume per 100 mm ribbon and its corresponding mass. The average
porosity of each of the three ribbons within a batch (n = 8) were very
similar, which confirms that the roller compaction process, in spite of
some slight heterogeneity within a ribbon, performed well and that
the process was robust. The SDs (n = 8), for the 8 segments of the rib-
bon, was in the range of 1 to 3%, which was comparable to the SDs ob-
tained in the experiments previously described, based on 12 randomly
collected ribbon fragments. There was no apparent relationship be-
tween the chosen gap size and the within-ribbon standard deviation.
To investigate whether any pattern exists in the porosity distribution
of a 100 mm ribbon, the porosity data for each ribbon fragment in
Table 5 are presented graphically in Fig. 7. As the sectioning was done
manually by hand, the dimensions of the individual fragments varied
and comparisons should be made with some caution. However, the

Table 4
Ribbon measurement results (n = 12) from the Mini- and Macro-Pactor® trials, respectively. All measurements were done by the laser system and the table shows raw data (volume and
mass) and the calculated ribbon porosity. The P-value is derived from the Mann–Whitney U test for comparison of two medians.

Batch # Equipment scale Ribbon raw data Ribbon porosity, %

Total volume, mm3 Total mass, mg Average St. dev. P-value

(n = 12) (n = 12) (n = 12) (n = 12)

#1 Mini-Pactor® 10,623 8,050 51.3 2.0 0.795

Gap: 4.0 mm Macro-Pactor® 12,675 9,631 51.5 1.8
Force: 3.0 kN/cm
#2 Mini-Pactor® 6,940 5,738 47.2 0.7 0.214
Gap: 2.0 mm Macro-Pactor® 7,206 6,152 45.6 3.3
Force: 3.0 kN/cm
#3 Mini-Pactor® 8,088 10,038 20.8 1.0 0.017
Gap: 2.0 mm Macro-Pactor® 6,722 8,195 22.0 1.7
Force: 11.0 kN/cm
#4 Mini-Pactor® 7,491 8,554 27.0 0.4 0.525
Gap: 4.0 mm Macro-Pactor® 6,166 7,005 27.5 3.0
Force: 11.0 kN/cm
#5 (CP) Mini-Pactor® 10,646 10,977 34.1 0.7 0.272
Gap: 3.0 mm Macro-Pactor® 10,824 11,013 35.0 2.7
Force: 7.0 kN/cm

Please cite this article as: Allesø, M., et al., Roller compaction scale-up using roll width as scale factor and laser-based determined ribbon porosity
as critical material attrib..., European Journal of Pharmaceutical Sciences (2015), http://dx.doi.org/10.1016/j.ejps.2015.11.001
8 M. Allesø et al. / European Journal of Pharmaceutical Sciences xxx (2015) xxx–xxx
Fig. 5. Plot showing the relationship between ribbon porosities from the Mini-Pactor® and
Macro-Pactor® experiments. Ribbons from each of the five levels have been manufactured
at identical process parameter settings on the Mini- and Macro-Pactor® (roll force and
gap). The two dashed lines outline the 95% confidence interval of the regression line.
graphs are useful for revealing potential systematic differences in the
porosity between the middle (e.g. fragments 3 to 6) and the edges
(e.g. fragments 1, 2 and 7, 8) of a ribbon. Although there was a tendency
for some ribbons to be more porous in the middle and less porous at the
edges, this pattern was not consistently observed within a batch. For ex-
ample, two of the ribbons of batch #4 show this pattern while a third
ribbon shows the exact opposite pattern. Therefore, for this experimen-
tal setup the heterogeneity in porosity seemed to be randomly defined
during the roller compaction process. This observation was in contrast
to other studies, which revealed some repeatable patterns in ribbon
density distribution across the roll width. However, direct comparisons
with studies from different research groups are difficult, since formula-
tion factors like filler compression properties and powder lubrication as
Fig. 6. Photograph of a Macro-Pactor® ribbon before and after sectioning with a trimming knife. Each ribbon segment has been numbered so that ribbons 1 and 8 represent the edges of the
whole ribbon with 4–5 representing the center (approximately).
Please cite this article as: Allesø, M., et al., Roller compaction scale-up using roll width as scale factor and laser-based determined ribbon porosity
as critical material attrib..., European Journal of Pharmaceutical Sciences (2015), http://dx.doi.org/10.1016/j.ejps.2015.11.001
well as process conditions (gap size, roll speed, roll width, and compac-
tor design) can influence the density distribution across the ribbon
width. Miguélez-Moran et al. (2009) applied micro-indentation,
among others, to measure the change in relative density across a
200 mm ribbon width manufactured on a lab scale instrumented roller
compactor using gravity feeding. The authors demonstrated a tendency
of all ribbons to be most dense in the middle (least porous) relative to
both edges. This difference was most pronounced for ribbons
manufactured at the largest gap (here 1.0 mm compared against
0.9 mm) and high roll speeds (6 rpm). The authors attributed this to
the friction between the powder and fixed side plate, inhibiting powder
pull-in at the edges and consequently less powder compaction at the
edges since the gap was fixed. The importance of the friction between
powder and side sealing material was confirmed by the addition of lu-
bricant, which improved the density distribution across the ribbon
width (Miguélez-Moran et al., 2008). Using NIR chemical imaging (at-
line) Khorasani et al. (2015) investigated the difference in relative den-
sity of an MCC-based formulation processed on a pilot scale roller com-
pactor with rolls mounted in the vertical position and powder feeding
with a single screw. They found ribbons to be more heterogeneous
when compacted at higher forces, with the edges being the least
dense. It is, however, difficult to interpret the density distribution
maps since these were provided as relative values based on the changes
in the slope and shift of the NIR spectrum baseline (i.e. scatter effects).
Guigon and Simon (2003) investigated the heterogeneity in density of
sodium chloride ribbons processed on a lab-scale roller compactor
equipped with 130 mm smooth rolls. They found the density distribu-
tion to be periodical and linked to the period of the screw feeder, and ul-
timately the uneven distribution of feed pressure. In a very recent study
Sullivan et al. (2015) demonstrated the application of terahertz spec-
troscopy for density mapping (via refractive index, RI) of ribbons
manufactured on a roller compactor with inclined roll configuration,
i.e. similar to the one used in the present work. Information on process
parameter settings in this study is very sparse, but translation of the RI
profiles into porosity generally revealed lower porosity in the middle
relative to the edges, which is in accordance with the research of others
described above, but not the present. The pattern, however, did not
seem to be constant as a function of process time, which is probably
due to the period of the feed screw described by Guigon and Simon
 M. Allesø et al. / European Journal of Pharmaceutical Sciences xxx (2015) xxx–xxx 9

Table 5
Porosities of the eight ribbon fragments, covering the entire 100 mm width of a Macro-Pactor ribbon. Results from 4 combinations of roll force and gap (both at 2 levels) are shown. (Three
ribbons were fragmented and analyzed per experiment, and all measurements were done by the laser system.) The table shows raw data (volume and mass), and the calculated ribbon
porosity.

Batch # Ribbon # Ribbon porosity, % Ribbon raw data

Ribbon segment # Average St. dev. Total volume, mm3 Total mass, mg
(n = 8) (n =8) (n = 8) (n = 8)
1 2 3 4 5 6 7 8
(edge) (edge)

#1 A 30.5 31.6 32.2 32.5 32.2 32.3 32.1 29.9 31.7 1.0 6,080 6,502
Gap: 2.0 mm B 30.6 31.2 31.4 31.5 32.0 32.3 32.9 30.4 31.5 0.8 6,483 6,951
Force: 7.0 kN/cm C 29.2 31.5 33.8 34.1 31.4 32.9 30.4 28.2 31.4 2.1 6,318 6,779
#2 A 33.9 36.8 37.4 37.2 38.9 37.8 35.8 34.0 36.5 1.8 7,910 7,873
Gap: 4.0 mm B 37.3 38.2 30.4 34.7 35.0 37.5 39.0 38.4 36.3 2.8 5,849 5,783
Force: 7.0 kN/cm C 37.5 37.1 35.9 35.5 37.9 37.4 36.7 36.9 36.9 0.8 4,912 4,854
#3 A 24.1 22.2 23.1 21.4 21.0 20.6 20.5 20.8 21.7 1.3 6,082 7,437
Gap: 2.0 mm B 22.2 22.7 24.9 23.1 23.0 21.0 19.0 18.1 21.8 2.3 6,665 8,143
Force: 11.0 kN/cm C 16.6 18.9 23.0 24.6 24.0 25.2 22.5 19.9 21.8 3.1 6,668 8,168
#4 A 26.8 27.0 30.0 30.6 30.0 30.8 26.9 20.3 27.8 3.5 5,989 6,741
Gap: 4.0 mm B 27.3 28.4 29.1 28.8 28.7 28.4 27.5 21.9 27.5 2.4 4,964 5,616
Force: 11.0 kN/cm C 32.7 29.5 29.1 26.3 26.5 26.8 27.2 29.6 28.5 2.2 5,578 6,267

(2003). In the present investigation, the period of the feed screw may
also explain the lack of a repeatable pattern in the porosity distribution
of the 100 mm ribbons plotted in Fig. 7. Considering the inherent high
sensitivity of a plastic material to deformation upon pressure, like the
MCC used here, these within-ribbon variations were deemed minor
from a practical point of view and the average porosity value of a
100 mm ribbon was very repeatable.
4. Conclusion
The major aim of this study was to investigate the hypothesis of rib-
bon porosity being scale-independent when using roll width as scale up
parameter, more specifically, that ribbon porosity is not affected by a
change of roll width from 25 mm to 100 mm at constant RC parameter
settings. A direct and rapid laser-based method was used to determine

Fig. 7. Porosities of the eight ribbon segments, covering the entire 100 mm width of a Macro-Pactor ribbon. Results from 4 combinations of roll force and gap (both at 2 levels) are shown.
(Three ribbons were sectioned and analyzed per experiment).

Please cite this article as: Allesø, M., et al., Roller compaction scale-up using roll width as scale factor and laser-based determined ribbon porosity
as critical material attrib..., European Journal of Pharmaceutical Sciences (2015), http://dx.doi.org/10.1016/j.ejps.2015.11.001
10 M. Allesø et al. / European Journal of Pharmaceutical Sciences xxx (2015) xxx–xxx
the porosity of the ribbons at-line. With a repeatability of 0.2%, and
excellent agreement with a well-established volume displacement
method, the laser-based method was indeed a powerful and elegant ap-
proach to acquire ribbon porosity rapidly (less than 2 min per ribbon).
The ribbon porosity was found to be scale-independent when com-
paring the average porosity of five groups of ribbon samples (each with
n = 12 samples) from the small-scale (Mini-Pactor®) to the large-scale
(Macro-Pactor®). The higher standard deviation of the measured po-
rosities of ribbons segments from the large-scale roller compactor was
attributed to minor variations in powder densification across the roll
width (100 mm), and is in agreement with reports from the literature.
This within-ribbon variability was not assessed on the smaller scale
Mini-Pactor® ribbons since each ribbon measured naturally represent-
ed the entire roll width (25 mm).
With the intention to reproduce ribbon porosity from one scale to
the other, process settings of roll force and gap size applied to the
Mini-Pactor® (and identified during formulation development) are
therefore directly transferrable to subsequent commercial scale produc-
tion on the Macro-Pactor® with same roll diameter. This creates a better
link between formulation development and technology transfer, and
decreases the number of batches needed to establish the parameters
of the commercial process.
Acknowledgments
The authors are thankful to Uffe Teis Svare and Jacob West for their
skilled contributions to the experimental work. Terry Chriss and Mi-
chael Hanisch are thanked for the technical discussions.
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