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A Novel Use of Friability Testing for Characterising Ribbon Milling Behaviour
Serena Schianoa, Chuan–Yu Wua*, Andreja Mirticb and Gavin Reynoldsb
a
Department of Chemical and Process Engineering, University of Surrey, Guildford, GU2 7XH, United Kingdom
b
Pharmaceutical Development, AstraZeneca, Macclesfield, Cheshire SK10 2NA, United Kingdom
Abstract
Dry granulation using roll compaction (DGRC) becomes increasingly adopted in the pharmaceutical industry
due to its unique advantage of not requiring liquid binder and a subsequent drying process. However the
DGRC process presents also some challenges, in particular, high fine fraction generated during the milling
stage significantly limits its application. Although the fines produced can be recycled in practice, it may lead to
poor content uniformity of the final product. At present there is a lack of mechanistic understanding of milling
of roll compacted ribbons. For instance, it is not clear how fines are generated, what are the dominant
mechanisms and controlling attributes and if any measurement technique can be used to characterise ribbon
milling behaviour. Therefore, the aim of this paper was to assess if ribbon milling behaviour can be assessed
using some characterization methods. For this purpose, friability was evaluated for ribbons made of
microcrystalline cellulose (MCC) powders using a friability tester that was originally developed for
characterising the tendency of pharmaceutical tablets to generate small pieces while being abraded. Granules
were also produced by milling of the ribbons and their size distributions were analysed. The correlation
between the fine fraction of the granules with ribbon friability was then explored. It was found that there was
a strong correlation between ribbon friability and the fine fraction of granules generated during milling. This
implies that friability tests can be performed to characterise ribbon milling behaviour, and ribbon friability
provides a good indication of the fraction of fines generated during ribbon milling.
Keywords: Friability, milling, fine fraction, roll compaction, granule size distribution, dry granulation
1. Introduction
Dry granulation using roll compaction (DGRC) is one of the commonly used agglomeration
processes in manufacturing a wide range of products, including pharmaceuticals, fine
chemicals and minerals. This technique was initially developed for the production of coal
briquettes at the end of 19th century (Simone and Guidon, 2003), but it has since been used
in many other industrial sectors. Typical DGRC processes involve two stages: i) roll
compaction in which powders are compacted through two counter-rotating rolls to form
ribbons or flakes; and ii) ribbon milling in which ribbons are milled into granules. The
primary objective of DGRC is to improve the performance and processibility of fine powders,
such as flowability, bulk density and content uniformity, so that products with consistent
properties and good quality can be manufactured.
Comparing to wet granulation, the main advantage of DGRC is that no liquid binder is
needed so that no drying operation is required. Hence DGRC is a preferred agglomeration
*
Corresponding Author. Tel: 01483683506. Fax: 01483 686581 Email: [email protected]
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process for formulations involving substances sensitive to moisture or heat (Herting and
Kleinebudde, 2007; Kaur et al., 2011; Wu et al., 2010; Seville et al., 2001). Moreover, DGRC
is also an easy-to-operate continuous manufacturing process so that process automation
and on-line process control can be readily implemented. Consequently batch-to-batch
variations can be avoided (Miguélez-Morán et al., 2008; Leuenberger, 2001), and product
quality can be improved and running cost can be reduced (Miller, 1994; Yu et al., 2013,
Bultmann, 2002, Kuntz et al., 2011).
Nevertheless, DGRC also has some limitations. Comparing to tablets produced by direct
compression, the tablets made with the granules produced in DGRC generally have lower
tensile strengths, i.e. there is a loss in tabletability (Herting and Kleinebudde, 2008, Patel et
al., 2008). Several attempts were made to explain this behaviour. For example, Malkowska
and Khan (1983) introduced the concept of ‘work hardening’ defined as the increase of
resistance to permanent deformation of a material with the amount of deformation, and
attributed the observed reduction in tabletability of pharmaceutical excipients after being
granulated to work hardening. Sun and Himmelspach (2006) argued that granule size
enlargement was primarily responsible for the reduction in tabletability. They showed that
tabletability of MCC powders reduced with increasing granule size. This behaviour was
attributed to the fact that, larger granules tend to pack less efficiently due to smaller
binding/contact areas, which led to a reduced tensile strength of the tablets.
Another limitation of DGRC is the generation of excessive small granules, which are also
known as ‘fines” or “fine granules” (Herting and Kleinebbudde, 2007; Inghelbrecht and
Remon, 1998). In practice, the fines may be recycled and re-granulated in order to improve
the yield and reduce the waste. However, recycling of fines can cause segregation problems
and large content variations in final products, as demonstrated by Sheskey et al. (1994) who
investigated compaction efficiency (defined as the ratio of weight retained on the 1 mm
sieve mesh to the weight passing through the 180 μm sieve) and tablet friability for
methylcellulose mixtures and showed that reducing the content of recycled fines led to an
enhancement of the tablet uniformity. Therefore, it is necessary to control and minimise the
generation of fines in the milling process. However, this has been scarcely investigated and
little is reported in the literature, except the work of Inghelbrecht and Remon (1998b), who
performed a controlled wetting process before roll compaction with an attempt to reduce
the amount of fines produced during milling. They then examined tablets produced using
dry compacted granules and those produced via a pre-compaction wet granulation with a
fluidised bed granulator, for which the compacts were dried before milling. It was shown
that the tablet quality (i.e. dissolution rate, tensile strength) was improved and there was a
significant decrease of dust during DGRC using the controlled wetting step, but no
alternative way to the use of liquid binder was found. Therefore, a better understanding of
the mechanisms associated with the generation of fines during ribbon milling is necessary in
order to improve the efficiency and robustness of DGRC.
Therefore, the aim of this study was to investigate the milling of roll compacted ribbons, in
particular, to explore the dependence of granule size distribution on the ribbon properties,
and to assess if any experimental technique can be used to characterise ribbon milling. For
this purpose, various grades of microcrystalline cellulose (MCC) were roll-compacted to
produce ribbons at different conditions. A friability tester that is widely used for
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determining the attrition tendency of pharmaceutical tablets was employed to measure the
friability of ribbons. In addition, ribbon porosities and size distributions of granules
produced using these ribbons were also measured. An attempt was then made to assess the
correlation between the granule size distribution and ribbon properties.
2. Materials and methods
2.1 Materials
Microcrystalline cellulose (MCC) of three different grades, namely Avicel PH 101, Avicel PH
102 and DG (FMC, Biopolymer, USA) were considered. The first two powders were of pure
component, but MCC DG is a newly formulated microcrystalline-based excipient composed
of 75% of MCC and 25% of anhydrous calcium phosphate. True densities of powders were
measured using a Helium Pycnometer (AccuPyc II 1340, Micromeritics, UK) while particle
size analysis was performed using a QicPic size analyser (RODOS, Sympatec, Germany). Each
experiment was repeated three times and the d10, d50, d90 were determined and given in
Table 1.
Table 1. True density and particle sizes of three powders considered
Material
True density
(Kg/m3)
d10 (μm)
d50 (μm)
d90 (μm)
MCC PH 101
1581.00±0.01
38.47 ± 0.14
75.07 ± 0.32
125.19 ± 0.97
MCC PH 102
1570.30±0.01
41.08±0.28
106.97±0.59
221.01±0.61
MCC DG
1785.60±0.01
35.58 ± 0.14
75.74 ± 0.22
157.64 ± 0.97
2.2 Roll compaction
All roll compaction experiments were performed using a custom-built gravity-fed roll
compactor that was also used by Bindhumadhavan et al. (2005), Miguélez-Morán et al.
(2008), Wu et al. (2010) and Yu et al. (2013). The roll compactor was composed of two
smooth stainless steel rolls of 46 mm in width and 200 mm in diameter. The gap between
the rolls was kept constant at 1.2 mm and the roll speeds were set at 1 rpm and 3 rpm in
order to explore the effect of roll speed on ribbon properties.
2.3 Ribbon porosity
Porosity (Φ) is generally defined as the fraction of the voids in a material and is determined
using Eq.(1).
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𝑝
Φ = 1 − ( 𝑒)
𝑝
(1)
𝑡
where ρe is the envelope density of the ribbon and ρt is the true density. The envelope
density was measured with an envelope density analyzer (GeoPyc 1360, Micromeritics
Instrument Corporation, USA) using fine sand, DryFlo, as the medium. Ribbons were cut into
square pieces of 10 mm X 10 mm before measurements. The true density was measured
using a Helium Pycnometer (AccuPyc II 1340, Micromeritics, UK). Each measurement was
repeated three times in order to check the reproducibility.
2.4 Ribbon friability
The friability (ξ) is defined as the fraction of mass abraded from the sample during the
friability test and is calculated as
𝑊𝑏− 𝑊𝑎
𝜉=(
𝑊𝑏
) × 100
(2)
where Wb is the initial sample mass and Wa is the mass of the abraded sample (i.e. ribbon)
after the friability test.
Ribbons friability was determined using a friability tester (F1, Sotax, Switzerland), as shown
in Fig. 1a ribbons of ca. 30 g were cut into square pieces of 30 mm X 30 mm (Fig. 1b) and
were abraded in the friability tester with a rotation speed of 50 rpm for 500 revolutions.
(a)
(b)
Fig.1 Ribbon friability testing: a) experimental setup and b) typical square ribbons used.
The loss in sample mass was determined by weighing the sample, carefully de-dusted using
a soft brush, before and after each experiment, and the friability was then calculated using
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Eq.(2). Each experiment was repeated three times and the mean value and the standard
deviation were determined.
2.5 Milling
The compacted ribbons were milled with a Frewitt granulator (SepSol Process Solutions,
USA) equipped with a mesh size of 2 mm, at an oscillating speed of 149 rpm and a
drum/mesh separation of 5 mm. The milling condition was fixed for all the experiments
reported here. The granule size distribution was analysed using a QicPic size analyser with a
RODOS dry dispersing unit (Sympatec, Germany). Each experiment was again repeated three
times and the d10, d50, d90 and span were determined, where the span was defined as:
𝑠𝑝𝑎𝑛 =
𝑑90−𝑑10
𝑑50
(3)
3. Results and discussion
3.1 Ribbon porosity
Figure 2 shows the porosity of ribbons made of different materials at two roll speeds. It can
be seen that, for all materials considered, the ribbon porosity increases as the roll speed
increases. This is consistent with the results obtained by Yu et al. (2012) who showed that,
using a roll compactor with a fixed roll gap, the maximum roll pressure decreases as the roll
speed increases. As a consequence, ribbons of higher porosities were produced at high roll
speeds.
At the same roll compaction conditions, the ribbon made of MCC PH102 has the highest
porosity, while the MCC DG the lowest one. This implies that slightly denser ribbons were
produced with MCC DG, comparing to other two grades of MCC powders considered. This is
due to the fact that MCC DG has a higher bulk density and higher tendency to plastic
deformation, comparing to MCC PH102 and PH101.
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50
1rpm
3rpm
Porosity (%)
40
30
20
10
0
MCC DG
MCC PH 101 MCC PH 102
Fig. 2 Porosities of ribbons made of various materials at different roll speeds (roll gap: 1.2 mm).
3.2 Ribbon friability
A typical example of ribbons before and after the friability test is shown in Fig. 3. It is clear
that the corners and edges of the square pieces were worn off during the friability test, as
the ribbons abrade with each other or with the walls of the friability testers. Abrasion is
observed to be the primary mechanism during the friability test reported here, as no
significant collision is observed.
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(a) Before the test
(b) After the test
Fig.3 Photographs of a ribbon piece made of MCC PH102 (a) before and (b) after the friability
test.
The ribbon friability for ribbons made of 3 materials at 2 roll speeds is presented in Fig.4. It
can be seen that, for a given material, the friability increases as the ribbon porosity
increases. The friability of the ribbons produced at a higher porosity is generally higher than
that with a lower porosity. In addition, the porosity appears to have a more significant
impact on the friability for MCC DG than MCC PH101 and MCC 102, as the ribbon friability
for MCC DG increased sharply when the porosity increased. Ribbons made of MCC PH101
are less friable than MCC PH102, as the porosities of MCC PH101 ribbons are generally
lower than that of MCC PH102 when they are roll-compacted at the same process
conditions (i.e. roll speed and roll gap), which is consistent with the observation of Herting
and Kleinebudde (2007). Although a higher friability is obtained with ribbons of higher
porosity (i.e. less dense packed) for a given material. It is also noticed that, being produced
at the same roll compaction condition, ribbons made of MCC DG generally have the highest
friability comparing to MCC PH101 and MCC PH102, even though the porosities of the
ribbons made of MCC DG are generally the lowest (i.e. are the densest ones) as shown in
Fig. 2. This implies that friability depends on not only the porosity but also other material
properties, such as particle size and chemical compositions.
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2
= 37%
= 33%
= 29%
3
= 27%
Friability (%)
4
=35%
= 33%
5
1
0
MCC DG
MCC PH 101
MCC PH 102
Fig.4 Friability of various ribbons considered.
3.3 Granule size distribution
The size distributions of the granules obtained from ribbon milling were analysed and
presented in Figs 5 and 6. In Fig. 5 the granule size distributions (frequency based on
volume, p3) obtained from ribbons with different porosities are shown. It is clear that, for
the granules made from ribbons of higher porosity, the fraction of coarse granules is lower
and a wider size distribution is obtained. Similarly to the friability behaviour observed in Fig.
4, for MCC DG, there is a more significant decrease in the fraction of coarse granules,
comparing to MCC PH 101 and MCC PH 102. Figure 6 shows the corresponding cumulative
size distribution based on volume (Q3). It can be seen that the cumulative size distribution
shifts towards the smaller granule size as the ribbon porosity increases. For instance, for
MCC DG granules produced from ribbons with a porosity of 27% (Fig. 6c), 10% of granules
has a size below 260 μm (i.e. d10=260), while d10 drops to 120 μm for granules made from
ribbon with a porosity of 33%. The corresponding d10, d50 and d90, for all samples
considered are shown in Figure 7, in which d10 indicates the small particle sizes, d50 the
mean granule size and d90 the large granule size. It can be seen from Fig. 7a that, for all
materials considered, d10 for the granules produced with ribbons with a higher porosity is
much lower, comparing to that with a lower porosity. Since a low value of d10 generally
implies a higher amount of fines being produced. It is hence suggested that more fine
granules will be produced from milling of ribbons with a higher porosity. When different
materials were processed at the same condition, d10 obtained with MCC DG is the lowest
among the materials considered, while d10 for MCC PH101 and PH102 are very similar. D50
(Fig.7b) and d90 (Fig.7c) for the granules produced with ribbons of different porosities and
different materials are comparable. Nevertheless, as the porosity increases, d50 appears to
decrease slightly but d90 increases marginally, for all materials considered. While the span
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becomes larger for granules obtained from ribbons of a higher porosity as observed in Fig.
8d.
(a) MCC PH101
(b) MCC PH102
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(c) MCC DG
Fig.5 Granule size distribution obtained from ribbons with different porosities and various materials
considered (roll gap: 1.2 mm).
(a) MCC PH 101
(b) MCC PH 102
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(c) MCC DG
Fig.6 Cumulative size distribution obtained from ribbons with different porosities and various
materials considered (roll gap: 1.2 mm).
200
= 37%
250
=35%
300
= 33%
d10 (m)
350
= 27%
400
= 29%
450
= 33%
500
150
100
50
0
MCC DG
MCC PH 101
MCC PH 102
(a)
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= 33%
=35%
= 29%
1400
= 37%
d50 (m)
1500
= 33%
1600
= 27%
1700
1300
1200
1100
1000
MCC DG
MCC PH 101
MCC PH 102
(b)
d90 (m)
= 37%
= 33%
=35%
= 29%
2200
= 33%
2400
= 27%
2600
2000
1800
1600
1400
1200
1000
MCC DG
MCC PH 101
MCC PH 102
(c)
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= 37%
= 33%
=35%
= 29%
span
1.5
= 27%
2
= 33%
2.5
1
0.5
0
MCC DG
MCC PH 101
MCC PH 102
(d)
Fig.7 Size distributions for granules obtained with ribbons with different porosities and various
materials considered (roll gap: 1.2 mm).
3.4 Correlation between GSD and ribbon friability
(a)
(b)
(c)
(d)
Fig. 8 Variation of GSD parameters (d10, d50, d90 and span) with ribbon friability.
The variation of GSD parameters with friability for various ribbons considered is shown in
Fig. 8. It can be seen that there are strong correlations between d10, span and the friability,
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while d50 and d90 for all cases considered is very similar. In particular, as the friability of the
ribbons increases, d10 decreases while the span increases. Moreover there is little variation
in d50 and d90. This indicates that granules produced with more friable ribbons will contain
smaller fine granules and have wider granule size distributions. This is consistent with the
results obtained from Weyenberg et al. (2005), who characterised ciprofloxacin granules
used to produce ocular tablets and found that more coarse granules were produced for
stronger (i.e. less friable) ribbons. This also implies that fine granules may be predominantly
produced by abrasion during ribbon milling. Therefore, ribbon friability characterisation will
be useful to indicate the fine fraction and the breadth of GSD during ribbon milling.
If the mean diameter of raw feed materials is used as the criteria to classify the fine granules
(i.e. fine granules are defined as those with a size smaller than the mean diameter of the
feed powder), the fine fractions for various granules produced are determined and plotted
against the friability in Fig. 9. It is clear that the fine fraction increases as the friability
increases for all materials considered. As aforementioned, the friability of ribbons increase
as the porosity increases. It is hence expected that the fine fraction will increase as the
porosity increases, as demonstrated in Fig. 10. Nevertheless, comparing Fig. 9 with Fig. 10, it
appears that there is a stronger correlation between the fine fraction and the friability, than
that between the fine fraction and ribbon porosity. This is attributed to the similar abrasion
mechanisms involved in the milling (Yu et al. 2013) and the friability testing. Furthermore,
ribbon friability can also be readily performed so the measurement can be used to evaluate
the production of fine granules during ribbon milling.
Fig. 9 Variation of granule fine fraction with ribbon friability.
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Fig. 10 Variation of granule fine fraction with ribbon porosity.
Conclusions
Roll compaction and ribbon milling using three different grades of microcrystalline cellulose
powders were performed, and ribbons were produced at two different roll compaction
speeds and milled into granules. Porosities of these ribbons and the size distributions of
granules produced were characterised. Furthermore, ribbon friability was measured using a
friability tester that was developed primarily for characterising pharmaceutical tablets. With
the novel use of the friability testing for ribbons, it was found that there is a strong
correlation between d10, the span and the ribbon friability. As the friability of ribbon
increase, the value of d10 decreases and the span increases, indicating that more friable
ribbons are milled into granules of higher fine fraction and larger span. Thus ribbon friability
testing could be a useful technique for characterising ribbon milling behaviour for ribbons of
sufficient strength. It should be noted that this method may not be suitable for brittle and
fragile ribbons, which deserves further investigation.
ACKNOWLEDGEMENTS
This work was supported by the IPROCOM Marie Curie initial training network, funded
through the People Programme (Marie Curie Actions) of the European Union's Seventh
Framework Programme FP7/2007-2013/ under REA grant agreement No. 316555. The
authors are grateful to FMC Chemicals prl, Brussels, Belgium, for provision of MCC powders
used in this study.
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