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GHENT UNIVERSITY
FACULTY OF PHARMACEUTICAL SCIENCES
Department of Pharmaceutical Analysis
Laboratory of Pharmaceutical Process Analytical Technology
Academic year 2013 - 2014
Continuous melt granulation: Effect of different binders upon
granule and tablet properties
Jochem VANCOILLIE
Master of Science in Industrial Pharmacy
Promoter
Prof. Dr. Apr. T. De Beer
Commissioners
Prof. Dr. J.P. Remon
Prof. Dr. R. Kemel
Prof. Dr. G. Van den Mooter
Dr. F. Kiekens
Supervisor
Apr. Tinne Monteyne
GHENT UNIVERSITY
FACULTY OF PHARMACEUTICAL SCIENCES
Department of Pharmaceutical Analysis
Laboratory of Pharmaceutical Process Analytical Technology
Academic year 2013 - 2014
Continuous melt granulation: Effect of different binders upon
granule and tablet properties
Jochem VANCOILLIE
Master of Science in Industrial Pharmacy
Promoter
Prof. Dr. Apr. T. De Beer
Commissioners
Prof. Dr. J.P. Remon
Prof. Dr. R. Kemel
Prof. Dr. G. Van den Mooter
Dr. F. Kiekens
Supervisor
Apr. Tinne Monteyne
COPYRIGHT
“The author and the promoter give the authorisation to consult and to copy parts of
this thesis for personal use only. Any other use is limited by the Laws of Copyright,
especially concerning the obligations to refer to the source whenever results are cited
from this thesis.”
Ghent, May 29th, 2014
Promoter Author
Prof. Dr. Apr. T. De Beer Jochem Vancoillie
ABSTRACT
The pharmaceutical industry has traditionally carried out its production processes in
a batch-wise manner. However, continuous processes, which are already implemented in
other industries, hold certain advantages over batch production, particularly in terms of
time- and cost-efficiency. The pharmaceutical industry is showing an increasing interest in
these continuous production processes, although certain challenges must be met before a
continuous production line can be implemented. An important bottleneck delaying this
implementation is the granulation step. A promising continuous granulation technique is
twin-screw granulation, applicable to both wet and melt granulation. Melt granulation, a fast
and simple one-step process, addresses some of the disadvantages of wet granulation, such
as hydrolysis and the presence of residual solvents. Despite these advantages, however, not
much research has been done in the field of continuous twin-screw melt granulation.
The aim of this research was to investigate whether different types of binder would
have a different influence on the granule and tablet properties. To this end, a model active
pharmaceutical ingredient was combined with four different binders, either being
amorphous or (semi)-crystalline and hydrophilic or hydrophobic, resulting in four
formulations. Design of Experiments was used do draw up four full factorial screening
designs, one for each formulation, and for the subsequent analysis and interpretation of the
effects the various process parameters had on the granule and tablet properties.
The amount of binder used during granulation was found to exert an effect on nearly
every response of each design, although the effects were greater when using a hydrophobic
binder. Hydrophilic binders were found to be influenced by the throughput, whilst the
temperature mainly had an impact on the design of stearic acid. The degree of screw fill was
found to have an important impact when using Soluplus, as inadequately filled screws
resulted in a mono-modal particle size distribution, which had a detrimental effect on all
responses. It was demonstrated that, although some similarities were found, each binder
influenced the granular and tablet properties in a different way.
ABSTRACT
De farmaceutische industrie maakt traditioneel gezien gebruik van batchgewijze
processen voor de productie van geneesmiddelen, ondanks het feit dat continue processen,
dewelke reeds geïmplementeerd zijn andere industrieën, bepaalde voordelen vertonen,
voornamelijk inzake tijds- en kosten-efficiëntie. De interesse vanuit de farmaceutische
industrie in deze continue processen nam de afgelopen jaren dan ook toe. Er zijn echter nog
enkele belangrijke knelpunten die moeten aangepakt worden vooraleer een continu proces
geïmplementeerd kan worden, waaronder het granulatieproces. Een veelbelovende
continue granulatietechniek is de twin-screw granulatie, op zowel natte als smeltgranulatie
toepasbaar. Smeltgranulatie is een snel en eenvoudig éénstaps-proces, dewelke bepaalde
nadelen van een nat granulatieproces, zoals hydrolyse of aanwezigheid van residuele
solventen, niet vertoont. Ondanks deze voordelen werd nog niet veel onderzoek verricht op
het gebied van continue twin-screw smeltgranulatie.
Het doel van dit onderzoek was het nagaan of verschillende soorten bindmiddel een
andere invloed zouden hebben op de granulaat- en tableteigenschappen. Om dit te
verwezenlijken werd een modelgeneesmiddel gecombineerd met vier verschillende
bindmiddelen, die ofwel amorf of (semi-) kristallijn waren en ofwel hydrofiele of hydrofobe
eigenschappen hadden. Dit resulteerde in vier verschillende formulaties. Experimenteel
design werd gebruik om voor elk van deze formulaties een full factorial screening design op
te stellen, dit te analyseren en te interpreteren om zo de effecten van de verschillende
procesparameters op de granulaat- en tableteigenschappen na te gaan.
De hoeveelheid bindmiddel die werd gebruikt tijdens de granulatie bleek een invloed
te hebben op bijna elke respons van ieder design, al waren de effecten meer uitgesproken
wanneer een hydrofoob bindmiddel werd gebruikt. Hydrofiele bindmiddelen werden dan
weer beïnvloed door de voedingssnelheid, terwijl de temperatuur vooral een invloed had op
het design van stearinezuur. De mate waarin de schroef gevuld was bleek een belangrijke
impact te hebben wanneer Soluplus werd gebruikt als bindmiddel. Wanneer de schroef
onvoldoende gevuld was, ontstond er een mono-modale verdeling van de deeltjesgrootte,
wat een nadelig effect had op de granulaat- en tableteigenschappen. Er werd aangetoond
dat, hoewel onderlinge gelijkenissen wel werden gevonden, elk bindmiddel een op andere
manier een invloed uitoefende op de granulaat- en tableteigenschappen.
ACKNOWLEDGEMENTS
I would like to dedicate this page to a number of people to whom I owe my sincerest gratitude for the
completion of this master dissertation, for this has not been an individual feat, but a collaboration of a group of
people. I was merely fortunate being allowed to partake in this project.
First and foremost, I would like to thank Prof. Dr. T. De Beer for giving me the opportunity to
participate in this research. Furthermore, I would like to thank him for introducing me to Design of
Experiments. The knowledge and skills that I obtained through these courses have already proven to be
valuable and this will undoubtedly be the case in my future career as well.
I would also like to extend my deepest gratitude to Apr. Tinne Monteyne for all the time, effort and
hard work she has put into this thesis. I am also thankful for the knowledge and expertise she shared, the
experience and scientific maturity I have gained and for the excellent guidance, whilst still giving me enough
space and responsibility to try and figure things out on my own. Besides thanking her professionally, I would
like to thank her for the friendship she has given me this past year, making this entire journey all the more
enjoyable. I could not have wished for a better supervisor.
Thanks are also extended to Mathias Indola, the Finnish exchange student I had the pleasure of
working with during the first 3 months of this research. Gratitude is also due to the entire staff of the
department of Pharmaceutical Technology, for helping me when and wherever I needed assistance. I would also
like to acknowledge my peers of “the fishbowl”, for all the good times we had during the year.
Gratitude is also extended to my friends, girlfriend and family, for always being there for me, for
motivating me to keep going and for simply being who they are: people you can count on when you need them the
most.
But all of this would not have been possible without the love and support of my parents. They have
given me the opportunity to do what I love and allowed me to reach my own potential. They made me the person
I am today and without them, I would never be where I am today.
Thank you.
TABLE OF CONTENTS
1. INTRODUCTION .......................................................................................................... 1
1.1. SCOPE ........................................................................................................................... 1
1.2. GRANULATION ............................................................................................................. 2
1.2.1. Wet granulation ........................................................................................... 2
1.2.2. Dry granulation ............................................................................................ 4
1.2.3. Melt granulation .......................................................................................... 4
1.3. TWIN-SCREW EXTRUDER ............................................................................................. 6
2. OBJECTIVE ................................................................................................................. 8
3. MATERIALS AND METHODS ........................................................................................ 9
3.1. MATERIALS ................................................................................................................... 9
3.1.1. Binders ......................................................................................................... 9
3.1.1.1. Polyethylene glycol 4000 .................................................................................. 9
3.1.1.2. Soluplus® ........................................................................................................... 9
3.1.1.3. Stearic acid ...................................................................................................... 10
3.1.1.4. Lunacera ......................................................................................................... 10
3.1.2. API ............................................................................................................. 11
3.1.2.1. Metoprolol tartrate ........................................................................................ 11
3.1.3. Additional excipients .................................................................................. 11
3.1.3.1. Aerosil® 200 .................................................................................................... 11
3.1.3.2. Magnesium stearate ....................................................................................... 11
3.1.3.3. Explotab® ........................................................................................................ 12
3.2. METHODS .................................................................................................................. 12
3.2.1. Design of experiments ................................................................................ 12
3.2.2. Twin-screw granulation .............................................................................. 14
3.2.2.1. General ........................................................................................................... 14
3.2.2.2. Experimental set-up ....................................................................................... 15
3.2.3. Characterisation of granules ....................................................................... 16
3.2.3.1. Friability .......................................................................................................... 16
3.2.3.2. Particle-size distribution ................................................................................. 16
3.2.3.3. Flow properties ............................................................................................... 17
3.2.3.4. True density .................................................................................................... 18
3.2.4. Tablet production ....................................................................................... 18
3.2.5. Characterisation of tablets ......................................................................... 18
3.2.5.1. Friability .......................................................................................................... 18
3.2.5.2. Tensile strength .............................................................................................. 19
3.2.5.3. Dissolution ...................................................................................................... 20
4. RESULTS AND DISCUSSION ....................................................................................... 20
4.1. DATA ANALYSIS .......................................................................................................... 20
4.2. GRANULES .................................................................................................................. 22
4.2.1. Influence on granule friability ..................................................................... 22
4.2.1.1. Common effects ............................................................................................. 23
4.2.1.2. PEG 4000 ......................................................................................................... 23
4.2.1.3. Soluplus ........................................................................................................... 23
4.2.1.4. Stearic acid ...................................................................................................... 24
4.2.1.5. Lunacera ......................................................................................................... 24
4.2.1.6. PEG 4000-Soluplus .......................................................................................... 25
4.2.1.7. PEG 4000-Stearic acid ..................................................................................... 26
4.2.1.8. Hydrophilic-Hydrophobic................................................................................ 27
4.2.1.9. Crystalline-amorphous ................................................................................... 27
4.2.2. Influence on particle size distribution ......................................................... 28
4.2.2.1. PEG 4000 ......................................................................................................... 29
4.2.2.2. Soluplus ........................................................................................................... 31
4.2.2.3. Stearic acid ...................................................................................................... 32
4.2.2.4. Lunacera ......................................................................................................... 33
4.2.2.5. PEG 4000-Soluplus .......................................................................................... 33
4.2.2.6. Stearic acid-Lunacera ...................................................................................... 34
4.2.2.7. Hydrophilic-Hydrophobic................................................................................ 34
4.2.3. Influence on flowability .............................................................................. 35
4.2.3.1. Common Effects.............................................................................................. 35
4.2.3.2. PEG 4000 ......................................................................................................... 36
4.2.3.3. Soluplus ........................................................................................................... 36
4.2.3.4. Stearic acid ...................................................................................................... 37
4.2.3.5. Hydrophilic-Hydrophobic................................................................................ 37
4.2.4. Influence on true density ............................................................................ 38
4.2.4.1. PEG 4000-Soluplus .......................................................................................... 38
4.2.4.2. Stearic acid ...................................................................................................... 39
4.2.4.3. Stearic acid-Lunacera ...................................................................................... 39
4.2.4.4. Additional analysis .......................................................................................... 39
4.3. TABLETS ..................................................................................................................... 40
4.3.1. Influence on tablet friability ....................................................................... 40
4.3.1.1. PEG 4000 ......................................................................................................... 41
4.3.1.2. Stearic acid ...................................................................................................... 42
4.3.1.3. Lunacera ......................................................................................................... 42
4.3.2. Influence on tensile strength ...................................................................... 44
4.3.2.1. PEG 4000 ......................................................................................................... 44
4.3.2.2. Soluplus ........................................................................................................... 45
4.3.2.3. Stearic acid ...................................................................................................... 46
4.3.2.4. Lunacera ......................................................................................................... 47
4.3.2.5. PEG 4000-Stearic acid ..................................................................................... 48
4.3.2.6. Soluplus-Lunacera ........................................................................................... 49
4.3.2.7. Crystalline-Amorphous ................................................................................... 49
4.3.3. Influence on dissolution ............................................................................. 50
4.3.3.1. Common effect ............................................................................................... 51
4.3.3.2. PEG 4000 ......................................................................................................... 51
4.3.3.3. Soluplus ........................................................................................................... 52
4.3.3.4. Stearic Acid ..................................................................................................... 52
4.3.3.5. Crystalline-Amorphous ................................................................................... 52
5. Conclusion ............................................................................................................... 54
6. BIBLIOGRAPHY ......................................................................................................... 56
ABBREVIATIONS
Ø: Diameter
API: Active Pharmaceutical Ingredient
Cc: Cubic centimetre
COST: Changing One Separate factor at a Time
CP: Center point
DoE: Design of Experiments
FV: Free Volume of the extruder in cc/diameter
MLR: Multiple Linear Regression
MPa: Megapascal
MPT: Metoprolol Tartrate
n=x: Test was performed x times
PLS: Partial Least Squared regression
PSD: Particle-Size Distribution
RNP: Residuals Normal Probability
Rpm: Rounds Per Minute
SG: specific gravity
VIP: Variable Importance for Projection
w/w: Weight/Weight
1
1. INTRODUCTION
1.1. SCOPE
Traditionally, the pharmaceutical industry has carried out its production of
pharmaceutical dosage forms in batch wise processes, whilst others, such as the food and
plastics industry, already left batch production behind in favour of continuous production for
reasons such as time- and cost-efficiency. If you keep in mind that the pharmaceutical
industry is a highly regulated industry and that the regulatory authorities are reluctant
towards changing a process after a product has been licensed, one can begin to understand
why the pharmaceutical industry has only made limited efforts to make the switch. Besides
this scepticism, the implementation of continuous processes has also been hindered by the
persistent misconceptions that continuous production is only practical for producing large
volumes, that it's not suited for production sites where the type of product being
manufactured changes often (or even daily, as is the case in a pharmaceutical production
plant) and that continuous processes are unable to consistently meet the high product
quality standards set within the pharmaceutical industry. (Plumb, 2005) (Vervaet et al, 2005)
Although, continuous processes have certain advantages over batch production.
Batch processes are poorly understood and hence still producing fluctuating and
unpredictable data, leading to a poor yield and impurities. Continuous processes are more
simplified, relatively well understood, easier to automate and are more easily controlled,
resulting in a higher yield and fewer impurities. Also, scaling up a batch process requires
expensive and time consuming optimization studies whereas continuous production can be
increased by numbering up or by increasing the run time. Additionally, continuous processes
are efficient energy users, in contrast to batch processes. This energy efficiency, combined
with the reduced waste, eliminated up-scale studies and savings in storage, floor space and
labour costs when switching to continuous production can significantly cut the production
costs, an advantage which pharmaceutical companies can’t ignore in a time of expiring
patents and competition from generic companies. (Plumb, 2005) (Vervaet et al, 2005)
2
Despite continuous production being the most favourable production method, it has
hardly been introduced. In the case of tablets for example, the most popular dosage form,
certain challenges must be met before one can implement a continuous production line. An
important bottleneck delaying this implementation is the granulation step.
(Vervaet et al, 2005)
1.2. GRANULATION
Granulation is an important unit operation, in which individual powder particles are
agglomerated into larger, multi-particle granules (in the pharmaceutical industry usually
described as an agglomerate between 0.1 mm and 2.0 mm), which are formed due to the
creation of bonds between the individual particles, either formed by mechanical force or
through the use of a binding agent. These granules exhibit better flow characteristics and
compressibility in comparison to the ungranulated powder, improving the overall
processability of the powder. Granules also possess a higher content uniformity and
segregation is less likely to occur due to a better control of the particle size. Other
advantages are the reduction of dust formation, which is particularly helpful when
processing toxic agents, and the reduction of the bulk volume, which makes the
transportation and storage of the powder somewhat easier. (Agrawal et al., 2011)
(Remon et al., 2011) (Vervaet et al., 2009)
1.2.1. Wet granulation
The most commonly used granulation technique is wet granulation, a technique in
which powders are mixed together with a liquid phase, which can either be a binder
solution, if the binder is already added to the liquid phase, or a solvent (usually water) if the
binder was added to the powder phase beforehand. Formation and growth of the granules
occurs in three steps. (Remon et al., 2011)
The first step is the wetting of the particles. The subsequent nucleation will depend
on the relative size of the liquid droplet. If the droplet is large in comparison to the powder
particles, the nucleation mechanism will be immersion. When the droplets are small,
3
however, nucleation will occur by distribution of the liquid on the surface of the powder
particles, which will then start to coalesce. (Agrawal et al., 2011) (Iveson et al., 2001)
(Scott et al., 2000)
Figure 1.1. Nucleation mechanisms in wet granulation. A) Distribution mechanism and
B) Immersion mechanism (Iveson et al., 2001)
This is followed by the growth step, either through the mechanism of coalescence,
which occurs when primary nuclei and agglomerates collide, or through layering, when fine
particles (which may be formed in the final step) collide and stick to the surface of a pre-
existing granule. The final step consists of breakage and attrition, occurring in respectively
wet and dried granules, so that wet granulation can be thought of as a balance between the
build-up and the breakdown of granules. (Agrawal et al., 2011) (Iveson et al., 2001)
(Scott et al., 2000)
Figure 1.2. Agglomeration mechanisms in wet granulation. A) Layering and B) Coalescence
(Iveson et al., 2001)
4
Because of the use of a solvent, a drying step afterwards is necessary. This excludes
moist- and temperature-sensitive pharmaceuticals from being agglomerated using this
technique due to the possibility of degradation. The additional drying step also increases the
cost and the complexity of the process. (Agrawal et al., 2011) (Remon et al., 2011)
1.2.2. Dry granulation
Dry granulation on the other hand does not use a liquid phase and therefore lacks a
drying step, which makes this technique very suitable for agglomerating moist- and
temperature-sensitive pharmaceuticals. It instead relies on a high pressure in order to
increase the surface area between the particles. When this high pressure alone isn’t enough
to cause agglomeration, a binder can be added to the mixture, which will form highly viscous
bridges between the particles. The technique’s major disadvantages are the generation of
dust, uncontrollable granulate size and irregular granulate properties and therefore it is not
considered to be the primary granulation method. (Kleinebudde, 2004) (Miller, 2005)
(Remon et al., 2011)
There are two techniques which are used in the pharmaceutical industry, namely
slugging and roller compaction. The former technique compresses the powder into a tablet
which in turn is milled into granules, and the latter technique uses two counter-rotating rolls
to form a compact that also gets broken down into granules. Roller compaction is the
preferred method since it is better controlled and has a greater production capacity.
(Kleinebudde, 2004) (Miller, 2005) (Remon et al., 2011)
1.2.3. Melt granulation
A third technique is melt granulation or thermoplastic granulation. Melt granulation
relies on a molten hydrophobic or hydrophilic binder to form liquid bridges between the
particles. Similar to the wet granulation technique, the binder can either be added to the
powder bed after it has been heated above its melting point via the spray-on or the pour-on
method, or the solid binder can be added to the powder mixture at room temperature, the
so-called melt-in method. The latter method eliminates the need of a liquid addition phase,
5
because the heating of the powder mixture above the melting point of the binder will
initiate the liquefaction of the binder and the subsequent granulation. (Remon et al., 2011)
(Van Melkebeke et al., 2006) (Vervaet et al., 2009)
The agglomeration of powder particles occurs either via distribution or immersion.
When the distribution mechanism occurs, the molten binder is distributed on the surface of
the primary particles. Those particles coalesce and form nuclei, which in turn undergo
coalescence to form agglomerates. In case of immersion, nuclei are formed when the initial
solid particles become immersed in the surface of a molten binder droplet. Both
mechanisms can occur simultaneously, yet one will be dominant. The distribution
mechanism will be the favoured mechanism when the binder droplet size is smaller than the
solid particle size or when a low-viscosity binder is used, while immersion will be promoted
when droplet size exceeds the solid particle size or when a high-viscosity binder is used.
Afterwards, the agglomerates are cooled down to room temperature, causing the liquid
bridges to solidify, yielding granules. (Abberger et al., 2002) (Mu et al., 2012)
(Schaefer, 2001) (Vilhelmsen et al., 2005) (Walker et al., 2006)
Melt granulation is a fast and simple one-step process which requires no additional
drying step, since there is no use of a solvent. As a result, there is no risk of product
hydrolysis and moisture-sensitive materials can be agglomerated using this technique. Also,
product toxicity and flammability are greatly reduced due to the absence of residual solvents.
Because there is no drying step, no transportation step from and to the dryer is needed,
eliminating the loss of product during this step. The cutting of these two steps also shortens
the processing time and reduces the necessary energy input. Of course, there is a risk of
thermal degradation of the active pharmaceutical ingredient at certain temperatures. This
risk, however, is minimized since most binders used in melt granulation have typical melting
ranges between 50-100 °C, which is well below the degradation temperatures of most API’s.
(Agrawal et al., 2011) (Schaefer, 2001) (Walker et al., 2006)
Currently, melt granulation is used in the pharmaceutical industry as a way to control
or modify the release of an API. Using a hydrophilic binder during the granulation process
will yield granules with an immediate drug release, whilst a hydrophobic binder yields
granules which can be used to produce sustained-release dosage forms. Melt granulation is
6
also applied as a technique to improve the dissolution and bioavailability of poorly water-
soluble drugs through the formation of solid solutions or solid dispersions, which generally
consists of a hydrophilic matrix (which can be amorphous or crystalline) and a hydrophobic
drug. Recently, melt granulation has also been used to improve the stability of moisture-
sensitive immediate release drugs and to enhance the tableting properties of poorly
compactible high dose drugs for both immediate-release and modified-release tablet
formulations. (Agrawal et al., 2011) (Dhirendra et al., 2009) (Kowalski et al., 2009)
(Lakshman et al., 2010) (Vasanthavada et al., 2010)
Several methods are currently being employed in the pharmaceutical industry to
perform melt granulation in a batch-wise manner, with high-shear mixers and fluidized bed
granulators being the ones most frequently used. A promising technique for continuous melt
granulation, however, is the use of a twin-screw extruder. (Abberger et al., 2002)
(Vervaet et al., 2009)
1.3. TWIN-SCREW EXTRUDER
Originally, extruders were developed and used as an industrial application in the
1930’s, mainly in the food and the plastics industry. Two types of extruders were developed:
single-screw extruders, which only have one screw, and twin-screw extruders, using two
side-by-side screws. Though single-screw extruders exhibit low investment costs and
mechanical simplicity, twin-screw extruders hold certain advantages over them, such as
easier material feeding, higher kneading potential, better dispersion capacities, less
tendency to overheat and shorter transit times. Two types of twin-screw extruders can be
distinguished, namely co-rotating and counter-rotating extruders, wherein the screws can
either rotate in the same direction or in the opposite direction, respectively. Co-rotating
extruders are most commonly used since they can be operated at higher screw speeds and a
higher output can be generated than counter-rotating extruders. Additionally, they allow
more flexibility in the screw design. (Kolter et al., 2011) (Mollan, 2003) (Patel et al., 2013)
It wasn’t until 1986 that Gamlen and Eardley introduced the twin-screw extruder in
the pharmaceutical industry as a wet granulation technique for producing paracetamol
extrudates. Lindberg et al. later used a similar twin-screw extrusion setup for the continuous
7
wet granulation of effervescent paracetamol preparations. Kleinebudde and Lindner studied
the influences of processing parameters on the twin-screw extrusion process as a
granulation tool. Keleb et al. compared twin-screw extrusion with a high shear mixer for the
wet granulation of lactose and concluded that extrusion (with a die) is a more efficient
technique, resulting in a higher yield and improved granule properties. A subsequent wet
sieving step of the discharged material, however, was still required in order to remove the
oversized fraction and obtain suitable granules. This step was eliminated through
modification of the screw design as well as the extruder setup. The discharge elements were
replaced with conveying elements and the die was removed. This resulted in a similar yield
compared to extrusion followed by the wet sieving step. (Gamlen et al., 1986)
(Keleb et al., 2002, 2004a,b) (Kleinebudde et al., 1993) (Lindberg et al., 1987)
(Van Melkebeke et al., 2006)
Besides wet granulation, twin-screw extrusion for melt granulation was also studied
using a similar extruder setup and modified screw design as used by Keleb et al. A veterinary
drinking water formulation with immediate drug release was developed by Van Melkebeke
et al. using polyethylene glycols (400 and 4000) as binders. The granulation temperature was
found to be a key factor influencing the process yield and high yield was only obtained at a
temperature near the melting point of the binder. A recent study by Van Melkebeke et al.
validated the twin-screw granulation process. It was reported that a single kneading block
was sufficient to obtain granules and one conveying element after the kneading block was
essential to improve the yield, based on the reduction of the oversized granules. Twin-screw
granulation was identified as a robust process, since a good mixing efficiency was obtained
independent of screw configuration, granulation time and granule size. (Djuric et al., 2009)
(Van Melkebeke et al., 2006, 2008)
Schaefer et al. did extensive research on the effects of the formulation and process
parameters on granule formation and granule properties during melt granulation in high
shear mixers and fluidized bed granulators. They found that binder rheology, and
consequently the type of binder, had a major influence on the agglomeration process and
granule properties. However, no such studies have been conducted for melt granulation
using a twin-screw extruder. (Schaefer et al., 2001) (Abberger et al., 2002)
8
2. OBJECTIVE
The pharmaceutical industry is showing an increasing interest in continuous
production processes, driven by various economic and technological reasons. An important
bottleneck delaying the implementation of continuous processes is the granulation step. A
promising continuous granulation technique is twin-screw granulation, applicable to both
wet and melt granulation. However, melt granulation has some advantages over wet
granulation, since it’s a fast and simple one-step process in which no solvents are used, and
therefore the drying and the transportation step to the dryer are not required, decreasing
the process time. Despite these advantages, not much research has been done in the field of
continuous twin-screw melt granulation.
The aim of this thesis is to investigate, to understand and to analyse whether
different types of binders, being hydrophilic, hydrophobic, crystalline and amorphous, would
have a different influence on granule and tablet properties. Acquiring fundamental
knowledge about the process is important in order to identify the critical process parameters
and their corresponding settings, leading to granules with optimal characteristics for further
downstream processing.
A model active pharmaceutical ingredient (API) will be combined with four different
binders, either being amorphous or (semi)-crystalline and hydrophilic or hydrophobic, to
investigate the effect of these types of binders on granule and tablet properties at various
levels of process parameters. Design of Experiments (DoE) will be used to draw up, analyse
and interpret the experiments from full factorial screening designs with 4 factors. General
characteristics between the binders will be sought after, in order to achieve a better
understanding of how the binders act and influence the various examined properties.
9
3. MATERIALS AND METHODS
3.1. MATERIALS
3.1.1. Binders
3.1.1.1. Polyethylene glycol 4000
Polyethylene glycols (PEG’s) or macrogols are polymers with the general formula
H(OCH2CH2)nOH, where the n represents the average number of oxyethylene groups. The
type of PEG is determined by a number indicating the average molecular weight. PEG 4000
(BUFA, Uitgeest, Holland) is a white or almost white solid, with a melting point around 53 °C
to 56 °C and is very soluble in water. (Handbook of Pharmaceutical Excipients, 2009)
Figure 3.1. Polyethylene glycol (Handbook of Pharmaceutical Excipients, 2009)
3.1.1.2. Soluplus®
Soluplus® is a polymeric solubilizer with an amphiphilic chemical structure, which was
particularly developed for solid solutions, but Soluplus® can also increase the bioavailability
of poorly soluble drugs.
Figure 3.2. Soluplus (BASF, 2010)
10
Soluplus® (BASF, Ludwigshafen, Germany) is a polyvinyl caprolactam – polyvinyl
acetate – polyethylene glycol graft copolymer (13 % PEG 6000/57 % vinyl caprolactam/30 %
vinyl acetate). It’s a free flowing white to slightly yellowish granule (mean particle size
approximately 340 µm) with a faint characteristic odour, with a glass transition temperature
of approximately 70 °C and is completely soluble in water. (Djuric, 2011)
3.1.1.3. Stearic acid
Stearic acid is a C-18 fatty acid, mainly used as a lubricant in making tablets and
capsules, but it is also used as an emulsifying or solubilizing agent. However, stearic acid can
also be used as a binder and for formulating sustained-release preparations.
Figure 3.3. Stearic acid (Handbook of Pharmaceutical Excipients, 2009)
Stearic acid (Mosselman, Ghlin, Belgium) is a mixture of stearic acid and palmitic acid,
with the content of stearic acid being not less than 40 %, and the sum of the two not less
than 90 %. It’s a hard, white, crystalline solid with a melting point around 69 °C to 70 °C.
Stearic acid is not water-soluble. (Handbook of Pharmaceutical Excipients, 2009) (Martindale,
2009)
3.1.1.4. Lunacera
Lunacera or microcrystalline wax is used as a stiffening agent in creams and
ointments, as a coating agent for solid dosage forms and for oral controlled-release matrix
pellet formulations. Lunacera (H.B. Fuller GmbH, Lüneburg, Germany) is a mixture of
straight-chain, branched-chain and cyclic hydrocarbons. It’s a white, waxy solid with a
softening range between 54 °C and 102 °C and is insoluble in water.
(Handbook of Pharmaceutical Excipients, 2009) (Martindale, 2009)
11
3.1.2. API
3.1.2.1. Metoprolol tartrate
Metoprolol tartrate (MPT) is a cardioselective beta blocker, used for the
management of hypertension, angina pectoris, cardiac arrhythmias, myocardial infarction
and heart failure. It’s also used for the management of hyperthyroidism and in the
prophylactic treatment of migraine. Metoprolol tartrate (Utag, Almere, The Netherlands) is a
white, crystalline powder with a melting point around 120 °C to 122 °C and is very soluble in
water. (Martindale, 2009)
Figure 3.4. Metoprolol tartrate (USP, 2008)
3.1.3. Additional excipients
3.1.3.1. Aerosil® 200
Aerosil® 200 or colloidal silicon dioxide is used in the pharmaceutical industry to
improve the flow properties of dry powders in processes such as tableting, capsule filling or,
as in this study, to improve the feeding characteristics of the API-binder mixture or the
premix. Aerosil® 200 (Evonik Degussa Corp., Essen, Germany) is a sub-microscopic fumed
silica with a particle size of about 15 nm and has a specific surface area of 200 m2/g. It is a
light, loose, bluish-white amorphous powder. (Handbook of Pharmaceutical Excipients, 2009)
3.1.3.2. Magnesium stearate
Magnesium stearate is used as a lubricant in capsule and tablet manufacture, usually
in concentrations between 0.25 % and 5 % w/w. In this study, we added 0.5% w/w
magnesium stearate to a certain amount of granules, with a mean particle size of 150 µm to
1400 µm, forming our tableting mixture. Magnesium stearate is a mixture of the magnesium
12
salts of stearic acid and palmitic acid, with the content of stearic acid being not less than
40 %, and the sum of the two not less than 90 %. It is a fine, white powder which is
practically insoluble in water. (Handbook of Pharmaceutical Excipients, 2009)
(Martindale, 2009)
3.1.3.3. Explotab®
Explotab® or sodium starch glycolate type A is used in oral pharmaceutical
preparations as a disintegrant in capsule and tablet formulations in a concentration between
2% and 8 % w/w. In this study, we added 5 % w/w of Explotab® to the tableting mixture.
Disintegration occurs by rapid uptake of water followed by rapid and enormous swelling.
Figure 3.6. Sodium starch glycolate (Handbook of Pharmaceutical Excipients, 2009)
Explotab®(JRS Pharma, Rosenberg, Germany) is the sodium salt of a cross-linked
partly O-carboxymethylated potato starch containing 2.8 % to 4.2 % sodium chloride. It is a
fine, white, very hygroscopic, free-flowing powder which forms a translucent suspension in
water. (Handbook of Pharmaceutical Excipients, 2009) (Martindale, 2009)
3.2. METHODS
3.2.1. Design of experiments
Experiments are often conducted by holding certain factors constant while altering
the level of another variable. This COST-approach (Changing One Separate factor at a Time)
leads to little information, doesn’t quantify interactions and leads to many experiments,
making it time-consuming and inefficient. Design of experiments, on the other hand, is a
statistical and mathematical technique used for planning, conducting, analysing and
13
interpreting carefully prepared sets of representative experiments, in which all relevant
factors are varied simultaneously. These well-planned experiments provide a great deal of
information about the effect of one or more factors on a response in a limited amount of
runs, rendering the experiments more time- and cost-efficient. (Eriksson et al., 2008)
(Lazic, 2004) (NIST/SEMATECH, 2013)
DoE can be implemented for three primary and consecutive experimental objectives,
namely screening, optimization and robustness testing. Screening designs are used for
determining the key factors in a process and their appropriate ranges. In an optimization
study, the optimal settings for each factor are defined. Finally, robustness testing is carried
out to assess how sensitive the responses are to minor changes or fluctuations in the factor
settings. (Eriksson et al., 2008) (Lazic, 2004) (NIST/SEMATECH, 2013)
Four full-factorial screening designs were created using the Modde 10.0 software
(Umetrics, Umeå, Sweden) in order to evaluate the influence of process variables on the
properties of granules and tablets for the different formulations. A full-factorial design is an
orthogonal design with experiments of all combinations of the factor levels, allowing the
main effects and all interactions to be clear of each other or non-confounded. Four two-level
factors were used in the design, along with three center points (CPs) in order to evaluate the
reproducibility.
Design Level Factor
Throughput Screw speed Temperature Binder concentration
PEG 4000/MPT
Low 0,350 100 30 5
Center point 0,625 225 44 12,5
High 0,900 350 58 20
Soluplus/MPT
Low 0,400 200 30 5
Center point 0,600 313 50 10
High 0,800 425 70 15
Stearic acid/MPT
Low 0,600 100 30 5
Center point 0,950 213 50 37,5
High 1,300 325 70 70
Lunacera/MPT
Low 0,400 200 30 5
Center point 0,650 313 45 32,5
High 0,900 425 60 60
Table 3.1. Factor levels and their values of the quantitative parameters
14
This resulted in 19 experiments (24 +3) per design. In order to determine the values
of each factor level, preliminary studies were performed. The different factors and their
levels can be seen in Table 3.1 for all five designs.
3.2.2. Twin-screw granulation
3.2.2.1. General
A twin-screw extruder consists out of two Archimedean-type screws within the barrel.
The barrel is divided into different temperature zones, in which the temperature can be
individually controlled. The barrel can also be divided into two segments: the feed segment,
where powder enters the barrel and a work segment, where the powder is mixed and
granulation occurs. At the end of the barrel, when used for hot melt extrusion, a die is
placed. For hot melt granulation, however, the die plate was removed to avoid excessive
densification of the material inside the extruder and thus yielding granules of acceptable size
for further processing. The screws can be constructed in any way desired, using three basic
elements, being conveying elements, kneading elements and combing mixer elements,
which are placed on the screw shaft. The conveying elements have a double helix and are
usually placed in the beginning and at the end of the screw to respectively convey the
material from the feeding zone to the working zone and to discharge the granules at the end
of the barrel. The kneading blocks are placed in the work segment where they mix the
powder and provide mechanical friction to induce or facilitate the melting of the binder. At
the end of the screws one can find the combing mixing elements, which break up lumps and
divide sticky particles. (Mu et al., 2012) (Serajuddin, 2011) (Van Melkebeke et al., 2006)
(Vercruysse et al., 2012) (Vervaet et al., 2009)
The material inside a twin-screw extruder is constantly transferred from one screw to
the other across the intermesh, thus describing a figure ‘8’ path. The mixing action is a
combination of compression and expansion with smearing effects between screw to screw
and screw to barrel wall. The energy to melt the polymer comes from the heated barrel, the
mechanical energy of the shafts and inter-particulate friction. A twin-screw extruder
operates at a temperature above the glass transition temperature of the binder, but below
the melting temperature of the drug substance. This, in combination with the relatively short
15
dwell time in the heated barrel, decreases the chance of thermal degradation of the active
ingredient. Also, the flow mechanics and heat transfer within an extruder are much more
localized and controlled in comparison to a high shear mixer or a fluidized bed.
(Mu et al., 2012) (Serajuddin, 2011)
3.2.2.2. Experimental set-up
The granulation experiments were performed using a co-rotating intermeshing twin-
screw granulation (Prism Eurolab 16, Thermo Fisher Scientific, Staffordshire, England)
without die plate. Before granulation, pre-blend mixtures (consisting of API, binder and 0.2%
Aerosil®) were made using a tumbler mixer (Inversina-Bioengineering, Wald, Switzerland),
mixing at 25 rpm during 10 minutes in order to obtain homogeneous mixtures. A Brabender
Flexwall 18 (Brabender Technologie GmbH & Co. KG, Duisburg, Germany) was used to feed
the mixtures gravimetrically. An equilibration period of 10 minutes was implemented at the
start of each run, before collecting the samples. This was done to allow for an adequate
screw filling, sufficient torque build-up and temperature build-up resulting from friction at
the kneading elements, resulting in a stable and constant output.
Figure 3.7. Screw design
A screw design with a total of 30 elements was used. First, there is a long conveying
zone, made up from 17.5 conveying elements, followed by a kneading zone consisting of 6
kneading blocks in a reverse 60° angle and finally another, short, conveying zone of 5
conveying elements. At the end of the screw one combing element was placed.
16
3.2.3. Characterisation of granules
3.2.3.1. Friability
The granule friability is a measure of the reduction in mass of the granules, due to the
formation of fragments when the granules are subjected to mechanical stress. This is
important in the transport and further processing of the granules. The granule friability was
determined in triplicate (n=3) by subjecting 10 g of granules (=m1), together with 200 glass
beads, with a mean diameter of 4 mm, to falling shocks inside the drum of a friabilator (PTF
E Pharma Test, Hainburg, Germany), rotating at 25 rpm for 10 minutes. The granule fraction
smaller than 250 µm was removed before determination in order to ensure similar starting
conditions. Afterwards, the beads were removed and the granules were sieved through a
sieve of 250 µm. The amount of granules retained on the sieve (=m2) was determined. The
granule friability (F), which is preferably as low as possible, was calculated as followed :
(European pharmacopoeia, 2011)
3.2.3.2. Particle-size distribution
The particle-size distribution (PSD) is an estimate of the relative proportions of the
different size fractions. A high yield fraction, this is the fraction between 150 µm and 1400
µm, is important in terms of cost-efficiency whilst also influencing the physical properties of
the powder, which in turn has an effect on other properties such as product uniformity and
bulk properties. The particle size distribution was determined (n=3) using a Retsch VE1000
sieve shaker (Haan, Germany). Approximately 50 g of granules was placed on a sieving tower,
consisting of 7 sieves (2000, 1400, 1000, 710, 500, 250 and 150 µm) and a collector, and was
sieved during 10 minutes at an amplitude of 2 mm. The mass retained on each sieve was
determined and used to define the particle size distribution. The fraction fines and oversized
were determined by the fraction below 150 µm and the fraction above 1400 µm,
respectively. (European pharmacopoeia, 2011)
17
3.2.3.3. Flow properties
The flow properties of a powder are an indication of how well a powder can flow like
a liquid, and are influenced by particle characteristics such as particle size, shape and size
variability. Flow properties are an important factor in a variety of operations, such as
granulation, where it plays a role in feeding, and tableting, where a constant and uniform
filling of the die is necessary to ensure the correct tablet weight and hardness. The
compressibility index or Carr index and the closely related Hausner ratio are simple and fast
methods of predicting powder flow characteristics and are both determined by measuring
the bulk volume and tapped volume of a powder. The bulk volume (V0) of 30 g granules was
recorded (n=3) in a 100 ml measuring cylinder, as well as the volume after 10 (V10), 500 (V500)
and 1250 (V1250) taps in a tapping machine (J. Englesman, Ludwigshafen, Germany). If the
difference between V500 and V1250 was greater than 2 %, the powder was subjected to
another 1250 taps (V2500). The Carr index and the Hausner ratio are calculated using the
following equations and the generally accepted scale of flowability is given in table 3.2. In
this study, the Hausner ratio was used to evaluate the flow properties of the granules.
(European pharmacopoeia, 2011)
Table 3.2. Scale of flowability (European pharmacopoeia, 2011)
18
3.2.3.4. True density
The true density of a powder is the ratio of the mass to the volume, exclusive of all
interparticulate voids and open intraparticulate pores. The true density of the granules was
determined (n=2) using an AccuPyc 1330 helium pycnometer (Micromeritics Instruments Inc.,
Norcross, United States), with helium being the preferred choice of gas due to its inertness,
small molecular size and high diffusivity. A precisely measured amount of sample (=m) was
placed in the test cell, filling at least 65 % of the cell. The pycnometer then determines the
volume occupied by the sample (=V) via pressure changes and calculates the true density by
means of the following formula (European pharmacopoeia, 2011):
3.2.4. Tablet production
The granule fraction between 150 µm and 1400 µm was mixed with 0.5 % (w/w)
magnesium stearate and 5 % Explotab® and mixed in a tumbling mixer (W.A. Bachshofen,
Basel, Switzerland) for 10 minutes. The tablets were produced automatically using an
eccentric tablet press (Korsch EKO, Berlin, Germany). The volume in the die was set by
adjusting the height of the lower punch in order to make tablets with an average weight of
115 ± 5 mg. The displacement of the upper punch into the die was controlled, resulting in
tablets being pressed at 1500 kg.
3.2.5. Characterisation of tablets
3.2.5.1. Friability
Similar to granules, tablets are also subjected to mechanical stress during
transportation, packaging and coating. The tablet friability was determined (n=1) using a
friabilator (PTF E Pharma Test, Hainburg, Germany) equipped with a drum as shown in
figure 3.8.
19
Figure 3.8. Drum for tablet friability (European pharmacopoeia, 2011)
The European pharmacopeia states that for tablets with an average weight below
650 mg, an amount of tablets should be used with an added weight of 6.5 g. However, in this
case it would lead to a high amount of tablets required, namely 57. The tablet friability was
determined (n=1) according to the European pharmacopeia 5.0, by subjecting 20 dust free
tablets (=m1) to falling shocks in a drum rotating at 25 rpm for 4 minutes. The tablets were
dedusted again and weighed (=m2). The percentage weight loss calculated with the following
formula was expressed as tablet friability and ideally does not exceed 1.0 %:
(European pharmacopoeia, 2005)
3.2.5.2. Tensile strength
The tensile strength of a tablet can be defined as the compressive force required to
break the tablet diametrically. The hardness or diametral crushing force (=F), tablet
thickness (=t) and tablet diameter (=D) were all determined (n=15) using a HT 10 automated
tablet testing system (Sotax, Basel, Switzerland). The tensile strength (=σx) can then be
calculated using the following equation (Pitt et al., 2013):
20
3.2.5.3. Dissolution
The dissolution curve can be defined as the fraction of the drug (present in the tablet)
which is dissolved within given timeframes. The dissolution was determined (n=3) using the
paddle method described in the European pharmacopoeia. A VK 7010 dissolution apparatus
with a VK 8000 sampler (Vankel Industries, New Jersey, United States) was used. Each of the
six dissolution vessels was filled with 900 ml of demineralized water, kept at 37 ± 0.5 °C using
a heater (Vankel Industries, New Jersey, United States). Each vessel contained one paddle
rotating at 100 rpm and a sampling probe. Samples (5ml) were taken at pre-set time
intervals (after 5, 10, 20, 30, 45, 60, 90 and 120 minutes for immediate-release forms, 0.5, 1,
2, 4, 6, 8, 12, 16, 20 and 24 hours for sustained-release dosage forms) using a VK 810
peristaltic pump (Vankel Industries, New Jersey, United States). A UV-1650PC double-beam
spectrophotometer (Shimadzu, Antwerp, Belgium) was used to determine the drug content
of each sample at 222 nm.
4. RESULTS AND DISCUSSION
4.1. DATA ANALYSIS
In the following sections 4.2 and 4.3, the results of the analyses are displayed through
effect plots. Before constructing these effect plots, the data were analysed in order to
estimate whether the model calculated by Modde® fits the data, to find and correct
anomalies and to transform the data when necessary. The models for all responses (except
for PSD) were calculated using multiple linear regression (MLR), which considers the
responses to be independent of one another. The model for PSD was calculated using partial
least squared regression (PLS), since the various fractions are not independent and in this
way their co-variances were taken into account. Hereinafter, a brief summary of the plots
that were analysed are given with their significance included.
The condition number is a measurement of the sphericity or orthogonality of a design,
calculated as the ratio of the largest and the smallest singular values of the X-matrix. All two-
level factorial designs, without CPs, have condition number 1, indication an orthogonal
design. A screening design with a condition number below 3 indicates a good design.
21
The replicate plot shows the variation in results for all experiments. Ideally, the
variability of the repeated experiments (CPs) is much lower than the overall variability and
the CPs are located in the middle of the values.
The histogram shows us the response’s distribution, which is preferentially a “bell
shaped” normal distribution. This plot also shows us if there is positive or negative skewness
and if the data has to be transformed, logarithmically or negative logarithmically,
respectively. It’s important that the Q2 value (the model’s predictive power) increases by
transforming, denoting an increasing predictability of the model.
The Summary of Fit plot is a summary of four basic parameters: R2, Q2, model validity
and reproducibility. R2 is a measure of how well the data fits the model. A value of 1
indicates a perfect model, with all points on line. However, it is easy to get arbitrarily close to
1, so it is more important to consider Q2 which measures the predictive power of the model
to predict the responses for new experimental conditions. A value above 0.5 is considered to
be good, above 0.9 is great. R2 will always be higher than Q2 but shouldn’t exceed it by more
than 0.2-0.3. The model validity, which is a test of diverse model problems, higher than 0.25
indicates a good model. When the model validity is lower, significant lack of fit is present in
the model, indicating a model imperfection. The reproducibility, finally, is the variation of
the replicates compared to overall variability. A value greater than 0.5 is warranted for a
good control of the experimental procedure.
The residuals normal probability (RNP) plot is a good tool for finding outliers. Also, if
all points are on a straight diagonal line, the residuals are normally distributed noise. If a
curved pattern is detected, this indicates incorrect transformation of the response.
22
4.2. GRANULES
4.2.1. Influence on granule friability
When examining the absolute values of the raw data, it’s apparent that the friability
of granules covers a large range, as can be seen in table 4.1, stretching from 0 % up to
almost 50 %. The maximum values of friability for PEG 4000 and Lunacera, both semi-
crystalline binders, were found when operating at a low throughput and low screw speed
using 5 % binder. When using PEG 4000 and Lunacera in a concentration of 5 %, granules
with a comparably high friability of about 35 % are yielded, as seen in figure 4.1. However, at
a high amount of binder, the friability all but disappears when Lunacera is used, whilst
friability for the PEG 4000 drops to about 22 %. So overall, the PEG 4000 design yields the
most friable granules. The design with stearic acid has yielded the granules with the lowest
overall friability. Attachment 1 gives an overview of the analysis of the raw data. These data
were primarily used to determine whether the selected model and transformations were
adequate.
Minimum Maximum Average
PEG 4000 15,63 43,33 29,63
Soluplus 5,13 31,67 13,25
Stearic acid 1,37 28,37 12,29
Lunacera 0,01 49,37 16,17
Table 4.1. Granule friability in percentage per design
Figure 4.1. Average friability at low and high binder concentration
0
5
10
15
20
25
30
35
40
low high
% F
riab
ility
Binder concentration
Friability granules
PEG 4000
Soluplus
Stearic acid
Lunacera
23
4.2.1.1. Common effects
For all designs, shown in figure 4.4, the amount of binder added during granulation
has a negative effect on the granular brittleness, meaning that as the binder concentration
increases, less fragile granules are formed. This was also observed by Gokhale et al. during
high-shear wet granulation. A possible explanation is that, since more binder was used, more
bridges were formed between particles, resulting in stronger granules. Although the effect is
common, the size of the effect differs for each design. Whilst the effect for Lunacera seen in
figure 4.4 seems large (-35 %), this is due to an increase of the binder concentration with 55 %
(5 % → 60 %), resulting in a ratio of 0,64. For PEG 4000 on the other hand, an increase to 20 %
binder results in 15 % less friability, for a ratio of 1,00. Furthermore, the effects of the
throughput and the screw speed are equal as well (except for respectively Soluplus and
stearic acid), namely the absence thereof. (Gokhale et al., 2005)
4.2.1.2. PEG 4000
The design of PEG 4000 showed three significant interactions. The first significant
interaction (shown in attachment 2) is between the throughput and the temperature. At low
temperatures, an increase in throughput has a negligible effect on the friability
(approximately 1.5 %), whilst at high temperatures (above the melting point), an increase in
throughput results in a reasonable decrease of the friability by 8 % due to higher level of
densification. The other two interactions, between the temperature and binder
concentration and between screw speed and binder concentration, will be discussed in
section 4.2.1.6. (Evrard et al., 1999)
4.2.1.3. Soluplus
An increase in temperature will result in a lower viscosity and an increase in friability
for the granules made with Soluplus as a binder. Because of this lower viscosity, Soluplus can
be better distributed among the particles, causing a thinner layer of binder. This may cause
thinner and more friable bonds. Moreover, the throughput has a negative effect on the
friability as well. This can be attributed to a higher level of densification due to a higher
screw fill, which was also observed by Dhenge et al.
24
FV: free volume of extruder (cc/Ø). SG: specific gravity of material (Martin, 2013)
The design of Soluplus revealed five additional significant interactions, two of which
will be discussed in section 4.2.1.6. The first interaction, between the throughput and the
screw speed (attachment 3), reveals that the throughput has an inconsequential effect on
the friability when operating at a low screw speed, because at this low parameter setting the
degree of screw fill will be sufficient, regardless of the throughput. At a higher screw speed,
however, a higher throughput will be required to assure that the screws are adequately
filled, as this will yield far less brittle granules than when the same screw speed is used
combined with a low throughput. This is in line with the main effect of throughput and the
idea that, at least for Soluplus, a well filled screw leads to less fragile granules (18 % lower
friability). The second and third interaction, between the throughput and the concentration
of Soluplus and between the screw speed and the temperature, were significant as well, yet
caused less important effects (respectively 6 % and 10 % difference in granule friability).
(Dhenge et al., 2011) (Martin, 2013)
4.2.1.4. Stearic acid
Beside the effect of amount of binder, two other main effects have a significant
negative effect on the strength of the granules when stearic acid is used as a binder, namely
the temperature and the screw speed. The yielding of stronger granules by using an
increasing screw speed has already been observed by Djuric et al. during wet twin-screw
granulation using polyvinylpyrrolidon (PVP) as a binder. They attributed this increase in
granular strength to an increase in mechanical stress when higher screw speeds were
applied.
4.2.1.5. Lunacera
Besides the common effect of binder concentration, no significant effects or
interactions were found to have an influence on the frailty of the granules from the Lunacera
design.
25
4.2.1.6. PEG 4000-Soluplus
For both hydrophilic binders, the interaction between the temperature and the
binder concentration was found to be significant. The interaction is depicted in figure 4.2 for
PEG 4000 and Soluplus and one can see that at low operation temperatures, an increase in
the PEG 4000 concentration has a large negative effect on the friability, going from 39 % to
19 %. In both designs, an increase in temperature at low binder concentrations gives
stronger granules, due to a decrease in viscosity and subsequent increase in binder
distribution and coalescence. When using a higher amount of binder, an increase in
temperature will yield weaker granules (similar to the main effect of Soluplus). The latter
effect is even more expressed for Soluplus. This is consistent with the main effects: the
negative effect of the binder concentration is larger than the positive effect of the
temperature on the granule friability, until the temperature rises to a value high enough to
nullify the negative effect of the binder concentration at that point.
Figure 4.2. Interaction plots of temperature and binder concentration for PEG 4000 (left) and Soluplus (right)
The interaction between the screw speed and the binder concentration, shown in
figure 4.3, is also significant for both designs, even though they have an opposite trend (note
on figure 4.4 that the screw speed has an insignificant, yet opposite effect on the friability
for PEG 4000 compared to Soluplus). When using PEG 4000, an increase in screw speed will
result in less friable granules at low concentrations of binder and in more friable granules at
high PEG 4000 concentrations. Meanwhile, for Soluplus, the concentration has no influence
on the friability at the lowest screw speed, whilst at a high screw speed, the friability
decreases when high amounts of Soluplus are used and increases at low concentrations.
26
Figure 4.3. Interaction plot of screw speed and binder concentration for PEG 4000 (left) and Soluplus (right)
For Soluplus, increasing the temperature will increase the friability, whilst increasing
the throughput will lower granular friability. This is also observed when PEG 4000 is used,
although through an interaction (attachment 2). This means that a temperature increase
when using PEG 4000 will result in more friable granules when the throughput is low, which
causes a longer residence time inside the barrel, prolonging the time available for the binder
to melt and become finely distributed and conversely that an increase of the throughput will
result in a reduction of granular friability when operating at a high temperature.
4.2.1.7. PEG 4000-Stearic acid
PEG 4000 and stearic acid, both crystalline binders, do not share any common effects
besides the binder concentration mentioned before. However, a few trends at the 5 %
binder concentration level can be found when comparing the two significant main effects for
stearic acid with interactions with the PEG 4000 design. The temperature has a negative
influence as a main effect for stearic acid, whilst the influence that the temperature has on
the granular strength for PEG 4000 is more equivocal, as it only plays a role in the
interactions between the temperature and the binder concentration or the throughput,
which can respectively be seen in figure 4.2 and attachment 2. From there one can see that
an increase in temperature will only result in relatively less brittle granules when a low
amount of binder is used or at a high throughput.
As for the screw speed, the second main effect for stearic acid, this factor also exerts
an interaction with the amount of PEG 4000 used. In the latter case, an increase in screw
speed shall result in a decrease of granular strength when low amounts of binder are used
27
(figure 4.3), similar to the temperature. Therefore, at low amounts of PEG 4000, it seems to
follow both main effects seen for stearic acid. At higher concentrations, however, the
difference between both binders may be due to the higher processability of stearic acid.
4.2.1.8. Hydrophilic-Hydrophobic
Whether using a hydrophilic or a hydrophobic binder, the friability of the granules is
primarily influenced by the amount of binder used during granulation. Using a higher
percentage of binder will result in stronger granules. However, when using a hydrophilic
binder in a high concentration, an increase in temperature will result in more friable
granules. At higher temperatures, however, an increase in throughput will result in stronger
granules, so increasing the throughput might compensate for the loss of granular strength
due to an increased temperature when using hydrophilic binders.
4.2.1.9. Crystalline-amorphous
No additional similarities or opposite effects were found between crystalline and
amorphous binders. No differences in friability between the two groups were found, as each
group displays a design with high friability, being PEG 4000 and Lunacera at a low
concentration, as the raw data revealed.
Figure 4.4. Main effect plots for friability of granules
-50
-40
-30
-20
-10
0
10
20
Throughput Screw Speed Temperature % Binder
% F
riab
ility
Main factor
Friability granules
PEG4000
Soluplus
Stearic acid
Lunacera
28
4.2.2. Influence on particle size distribution
Particles can be classified in three fractions, according to their size: the yield-fraction (0,150-
1,4 mm) which is the fraction that will be used to make the tablets, the oversized fraction (>
1,4 mm) and the fines (< 0,150 mm). Table 4.2 gives a small overview of the yield per design.
Evaluation of the raw data reveals that the maximum possible yield is significantly lower
when using a crystalline binder. For the hydrophilic binders, the lowest yield was acquired at
a low amount of binder, whilst for the hydrophobic binders the highest yield was recorded
when using 5 % binder, as seen in figure 4.5. On average, the yield at 5 % binder
concentration was somewhat comparable for PEG 4000, Soluplus and stearic acid
(respectively 62 %, 68 % and 73 %), whilst for Lunacera the average yield amounts to 93 %,
indicating that Lunacera has the highest binding capacity.
Minimum Maximum Average
PEG 4000 47,24 81,88 68,58
Soluplus 48,64 96,25 70,84
Stearic acid 4,47 77,47 53,86
Lunacera 23,34 95,21 71,94
Table 4.2. Yield in percentage per design
Figure 4.5. Yield per run. Runs with 5% binder are 1 to 8
0
10
20
30
40
50
60
70
80
90
100
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
% Y
ield
Run
Yield per run
PEG 4000
Soluplus
Stearic acid
Lunacera
29
Since the three fractions are dependent on one another, PLS was used to determine
which factors and interactions have an effect on these three fractions. One statistic that
describes the contribution of a factor to the model is the Variable Importance for Projection
or VIP. Another statistic which can be used to further determine the impact of a factor on
the response is the regression coefficient. When a variable has a small coefficient (in
absolute value), which makes a limited contribution to the response, and a small VIP (< 0,8
as described by Wold), the variable can be regarded as not impactful on the model.
(Wold, 1994)
First, these non-impactful factors were determined. The second step involved
screening which of the remaining impactful factors had a large enough effect on the
outcome to be deemed relevant. Thirdly, this was visually interpreted using PLS loadings
plots. On these plots, which can be found in attachments 5 to 8, a straight line is drawn
through the origin and the response that is being examined. On this line, the distance of a
factor or interaction to the origin is indicative of the impact the factor has on the response.
The side the factor has with respect to the response is indicative of whether the effect of the
factor is directly or inversely proportional to the response. These distances give a visual
representation of the impact of the factor on the response. The closer the loading is to the
origin, the smaller the impact the factor has. Only the largest effects and interactions are
discussed in the following sections.
4.2.2.1. PEG 4000
The most influencing factor on the yield was found to be the binder concentration. A
higher yield is obtained when a higher concentration of PEG 4000 is used due to a decrease
in the amount of fines. Because more binder is used, less ungranulated powder remains. This
was also seen by Walker et al. Increasing the throughput also results in a higher yield and a
lower amount of fines, but has the largest effect on the oversized fraction. The opposite was
described by Dhenge et al. during wet twin-screw granulation, namely that an increase in
feed rate results in smaller particles due higher attrition due to torque build-up. However,
this torque build-up leads to an increase in temperature (figure 4.6) above the melting point
of PEG 4000, which leads to an increase in particle size, as observed by Van Melkebeke et al.
(Dhenge et al., 2011) (Van Melkebeke et al., 2006) (Walker et al., 2006)
30
Figure 4.6. Effect of throughput on torque and actual temperature
Two interesting interactions were revealed as well. The first interaction is between
the screw speed and the throughput. At a low throughput, an increase in screw speed will
result in a lower degree of screw fill, lowering the compaction and resulting in more
ungranulated powder. On the other hand, increasing the screw speed combined with a high
throughput will increase the yield, due to a small increase in temperature caused by friction
due to the rapidly rotating screws. The opposite then happens for the fraction of the fines,
since these fractions are interdependent. Figure 4.7 shows both interaction plots side by side.
Figure 4.7. Interaction plots of throughput and screw speed for PEG 4000
-15
-10
-5
0
5
10
15
PEG 4000 Soluplus Stearic acid Lunacera
Effe
ct
Binder
Effect of throughput on torque/actual temperature
Torque
Temperature
31
The other interaction is between the throughput and the amount of binder
(attachment 9). This interaction shows us that the effect of the throughput on the oversized
particles and the fines is dependent on the amount of binder used. An increase in binder will
always result in an increase in yield, however this effect is more pronounced at a low
throughput, possibly attributable to a longer residence time. On the other hand, the
throughput plays an important role, but only at low binder concentrations. This might be
due to an insufficient amount of binder to form strong granules, thus needing more
compaction via throughput, resulting in a higher mean particle size, which explains the
increase in yield and oversized fraction.
4.2.2.2. Soluplus
Raw data analysis revealed that, when Soluplus was used as a binder, high amounts
of oversized particles were formed regardless of the binder concentration. This might be
attributable to the high binding capacity of Soluplus, as can be concluded from the study
performed by Djuric et al. in 2011. The screw speed, as documented before by Dhenge et al.,
has a slightly positive effect on the yield, lowering the amount of fines and oversized
particles due to the shorter residence time, lower screw fill and subsequent reduction in
growth of granules. An increase in binder concentration will also heighten the yield, due to
less formation of fines. The throughput, however, exerts the largest influence on the yield.
As the material throughput is increased, it causes a higher screw filling degree which results
in a higher particle size, conform with the observations made by Djuric et al. in 2010.
The interaction between the throughput and the screw speed (shown in figure 4.8)
also has an effect that should not be overlooked. When granulating with Soluplus at a low
throughput and high screw speed, the screws are insufficiently fed. This starvation causes
the yield to increase markedly, whilst the amount of oversized and fines drop to nearly 0 %.
This causes the particle size distribution to shift from a bimodal distribution to a mono-
modal distribution, in which the fraction between 150 µm and 500 µm comprises more than
75 % of the granules. This has a terrible impact on the granule and tablet properties such as
granular friability, flowability, tensile strength and dissolution, as will be demonstrated in
later sections. (Dhenge et al., 2010) (Djuric et al., 2010, 2011)
32
Figure 4.8. Interaction plots of throughput and screw speed for Soluplus
4.2.2.3. Stearic acid
The amount of binder used has a negative effect on the yield and the amount of fines,
due to the formation of big, oversized granules. The same is observed for the temperature,
where an increase in temperature (above the melting point of stearic acid) will result in a
lower viscosity, causing the granules to shift from the capillary stage to the droplet stage.
This is also shown (figure 4.9) in the interaction between both factors.
Figure 4.9. Interaction plots of temperature and binder concentration for stearic acid
33
At a low concentration of stearic acid, an increase in temperature will not result in a
relevant change of yield or oversized particles. However, when high amounts of binder are
used, an increase of temperature will result in too much liquid-phase binder, causing droplet
formation. Furthermore, the screw speed exerts a similar but smaller effect on the yield,
oversized fraction and amount of fines as the binder concentration and the temperature,
possibly through a small increase of temperature due to friction.
4.2.2.4. Lunacera
The amount of Lunacera used during granulation negatively affects the yield and the
amount of fines, due to the formation of oversized granules. The yield can be increased by
granulating at a higher temperature. The interaction, shown below in figure 4.10, between
both factors reveals that, when using 5 % Lunacera, the temperature has no effect. But when
granulating with a high amount of Lunacera, high temperatures should be used in order to
increase the yield.
Figure 4.10. Interaction plots of temperature and binder concentration for Lunacera
4.2.2.5. PEG 4000-Soluplus
For both binders, increasing the amount of binder used during granulation will result
in a higher yield, mainly because of the decrease in the amount of fines. Furthermore, the
screw speed also exerts an effect in both designs, either through a main effect when using
Soluplus or through an interaction when using PEG 4000. Operating at a higher screw speed
34
will result in a higher yield fraction for Soluplus. For PEG 4000, this is only the case when the
increase in screw speed happens when granulating at a high throughput. The main effect of
the throughput is significant as well, albeit opposite. Whilst for PEG 4000 an increase in
throughput results in a higher yield, due to a higher compression to compensate for the
lower binding capacity, this augmentation will result in a lower yield when Soluplus is used,
due to the formation of oversized particles attributable to the high binding capacity of
Soluplus.
4.2.2.6. Stearic acid-Lunacera
Both stearic acid and Lunacera are used in matrix formulations. Based on their
processability, very large amounts of binder were used in both designs. These high amounts
of hydrophobic binder, however, adversely affect the yield and the amount of fines through
the formation of large amounts of oversized granules. The temperature has a substantial
negative effect on the yield for stearic acid, whilst for Lunacera the factor has a less
pronounced, positive effect.
4.2.2.7. Hydrophilic-Hydrophobic
Hydrophilic binders share the positive effect that an increase in amount of binder
results in a higher yield, accompanied with a reduction in amount of fines. However, this
increase in yield is not due to the hydrophilic nature of the binder, but rather because they
do not form matrix systems. Furthermore, the granule yield containing a hydrophilic binder
is also influenced by the throughput during granulation, although the effect is opposite for
PEG 4000 and Soluplus. The amount of oversized granules, however, will increase as the
throughput increases, regardless of the kind of hydrophilic binder. Both hydrophilic binders
are influenced by the degree of screw fill, although for PEG 4000 this results in more fines,
whilst for Soluplus this leads to mono-modal particle size distribution.
The amount of hydrophobic binder also influences the yield, however in a negative
fashion. Again, this is not because of the hydrophobic characteristics of the binder but rather
a consequence of the high concentrations of stearic acid and Lunacera when formulating a
matrix system. An increase in the concentration will result in a vast build-up of oversized
agglomerates, so it is advised to use a low concentration of hydrophobic binder in order to
35
maximise the yield fraction. The temperature can also influence the yield of granules made
with hydrophobic binders. This effect, however, is much larger and negative for stearic acid,
whilst for Lunacera a small positive effect is observed. The reason behind this is two-fold.
The first reason is that stearic acid has a melting point of 69-70 °C, so at 70 °C or
above, the binder will be completely molten and can cause the transition of the granule
saturation from the capillary stage to the droplet state, promoting uncontrollable granule
growth. Lunacera on the other hand has a glass transition temperature of 54-102 °C,
meaning that at 60 °C the binder will have only softened partially. The second reason is that
the amount of stearic acid used is higher than the amount of Lunacera, meaning that more
polymer is available for the formation of granules.
4.2.3. Influence on flowability
The raw data of the Hausner ratio values show that the flowability ranges from
passable to excellent when using the limits found in table 3.2. Stearic acid is the only design
yielding granules of at least fair to good flowability, the other 3 designs at least have one
experimental run which yielded granules with only passable flowability. Table 4.3 gives an
overview of the maximum and minimum Hausner ratio’s per design, as well as the average
ratio. In attachment 10, an overview is given of the analysis of the raw data.
Minimum Maximum Average
PEG 4000 1,123 1,300 1,187
Soluplus 1,087 1,338 1,176
Stearic acid 1,098 1,188 1,147
Lunacera 1,081 1,274 1,139
Table 4.3. Hausner ratio per design
4.2.3.1. Common Effects
For all designs but Soluplus, the binder concentration had a statistically significant
negative effect on the Hausner ratio, indicating that the yielded granules exhibit better
flowing properties when higher amounts of binder were used. This improvement in
flowability could be attributed to the decrease in the amount of fines when increasing the
binder concentration, since small particles tend to be more cohesive. This was also seen by
36
Yadav et al, who used PEG 4000 as a binder for the melt granulation of indomethacin. The
reason why this effect is not significant with Soluplus may be that the amount of binder used
was too low to expose this effect. It was also observed that the runs yielding granules with a
good flowability (Hausner ratio 1,00 – 1,18) had a wide particle size distribution, although it
was also observed that a wide distribution did not warrant a good flowability.
(Yadav et al., 2009)
4.2.3.2. PEG 4000
The throughput has a negative effect on the Hausner ratio when PEG 4000 is used,
thus improving the granular flowability.
4.2.3.3. Soluplus
The throughput has a direct and indirect influence on the flowability of granules
yielded from the Soluplus design. Increasing the throughput will result in better flowing
granules, but Soluplus has a significant interaction, depicted in figure 4.11, between the
throughput and the screw speed. The flowability is not influenced at a low screw speed,
however at high screw speeds an increase in throughput results in a considerable decrease
of the Hausner ratio. This could be due to a decrease in surface roughness or a more
spherical shape caused by a higher degree of densification following the higher degree of
screw fill, as observed by Dhenge et al. These experiments are still in progress and could not
be included in this thesis.
Figure 4.11. Interaction plot of throughput and screw speed for Soluplus
37
It was observed that four samples exhibited Hausner ratios of 1,30 or above. These
four samples were granulated at a high screw speed and at a low throughput, thus at a low
degree of screw fill, causing the particle distribution to become mono-modal when using
Soluplus (see 4.2.2.2).
4.2.3.4. Stearic acid
When looking at the effect plots in figure 4.12, one can observe that even though all
four main effects are significant for the design using stearic acid, the effects are rather small
and thus will not greatly influence the overall flowability. This helps explain why stearic acid
produces granules with overall good to excellent flowability and it should be taken into
account that in future optimisation studies, the influence of the process parameters on the
granular flowability is of less importance when using stearic acid.
4.2.3.5. Hydrophilic-Hydrophobic
The flow properties of the granules produced with a hydrophilic binder are positively
influenced by an increased throughput, due to the aforementioned thorough densification
within the barrel because of a higher degree of screw fill. Furthermore, an increase in
throughput results in a broadening of the particle size distribution. For PEG 4000, the
distribution broadens due to an increase in yield and oversized particles and a decrease in
fines. For Soluplus, however, the broadening of the distribution is due to an increase of the
oversized fraction and a lower yield. It was apparent that the stearic acid design and the
Lunacera design produced granules with overall good flow properties. Because both
hydrophobic binders have a low viscosity, they produce more spherical granules, increasing
the flowability. This was also observed by Schaefer et al. and was attributed to a higher
surface plasticity, making the rounding of the agglomerates easier. No further generalities
were discovered, however, some noteworthy trends were observed. For the granules
granulated with 5 % stearic acid, a better flowability is observed when granulating at a high
throughput due to an increase in yield and lower oversized fraction. However, at 70 % binder
concentration, less yield and more oversized particles are obtained when operating at a
higher throughput, resulting in a slightly lower flowability. For Lunacera, the throughput had
no effect on the flowability. (Schaefer et al., 1996)
38
Figure 4.12. Main effect plots for flowability of granules
4.2.4. Influence on true density
An analysis of the raw data for true density is less straight forward, since there are no
good or bad values for this response. Nevertheless, table 4.4 provides a summary of the raw
data, which reveals that the effects of the process parameters have only a small effect on
the true density for the PEG 4000 and Soluplus design, as can be seen from the difference
between the tabulated values below. Figure 4.14 confirms this, as it shows that most
significant effects do not induce a change of more than 2 % for these designs. Attachment 12
presents the results of the raw data analysis. Data point 14 from the PEG 4000 design was
deleted as it was an outlier.
Minimum Maximum Average
PEG 4000 1,213 1,222 1,217
Soluplus 1,171 1,214 1,193
Stearic acid 0,970 1,197 1,102
Lunacera 1,010 1,193 1,100
Table 4.4. True density in g/cm3 per design
4.2.4.1. PEG 4000-Soluplus
The true density of the granules obtained when granulating with PEG 4000 or
Soluplus as a binder is influenced by the throughput. Moreover, PEG 4000 has a significant
-0,2
-0,15
-0,1
-0,05
0
0,05
0,1
0,15
0,2
Throughput Screw Speed Temperature % Binder
Hau
sne
r ra
tio
Main factor
Flowability granules
PEG4000
Soluplus
Stearic acid
Lunacera
39
interaction between the screw speed and the temperature. These effects, however, are so
small (less than 1 % for PEG 4000 and 2 % for Soluplus) that they are negligible.
4.2.4.2. Stearic acid
The temperature negatively influences the true density of the granules obtained by
using stearic acid. However, this is only the case when high amounts of binder are used, as
evidenced by the interaction between the temperature and the binder concentration, which
is shown in figure 4.13. This might be caused by a decrease in viscosity of the binder due to
the increased temperature, which can facilitate the inclusion of air inside the granules.
4.2.4.3. Stearic acid-Lunacera
The amount of binder used has a negative influence on the true density for both
stearic acid and Lunacera. Their respective densities are 0,980 g/cm3 and 0,928–0,941 g/cm3,
whilst the density of metoprolol is 1,030 g/cm3. Given the high amount of binder used in
these designs, this explains why the amount of binder negatively influences the true density
of the resulting granules. (Handbook of Pharmaceutical Excipients, 2009) (Guidechem, 2012)
Figure 4.13. Interaction plot of temperature and binder concentration for stearic acid
4.2.4.4. Additional analysis
To rule out a possible masking effect on the true density of the high amounts of
binder used in the stearic acid and Lunacera designs, the effects were also investigated at
the 5% binder level. The results can be seen in attachment 13. However, this analysis did not
40
reveal any new effects, besides confirming that at a low binder concentration, the
temperature has no influence on the true density.
Figure 4.14. Effect plots for true density of granules
4.3. TABLETS
4.3.1. Influence on tablet friability
Analysis of the raw data, of which an overview can found in table 4.5, reveals that the
designs using Soluplus and stearic acid as binder exhibit no tablets with a friability above
1.0 %, the limit of weight loss that ideally should not be crossed. Both the designs with PEG
and Lunacera as binders each have runs, all at the 5 % binder concentration level, with tablet
friability above 1.0 %, this due to capping of the tablets. Overall can be concluded that
sufficiently low tablet friability was achieved with all binders.
Minimum Maximum Average
PEG 4000 0,112 3,000 0,646
Soluplus 0,166 0,545 0,367
Stearic acid 0,250 0,532 0,423
Lunacera 0,018 3,000 0,605
Table 4.5. Tablet friability in percentage per design
Attachment 15 presents an overview of the results of the raw data analysis. The data
for tablet friability in the Lunacera design required logarithmic transformation in order to
-0,25
-0,2
-0,15
-0,1
-0,05
0
0,05
Throughput Screw Speed Temperature % Binder
Tru
e d
en
sity
(kg
/l)
Main factor
True density
PEG4000
Soluplus
Stearic acid
Lunacera
41
achieve more normally distributed data. Note that the effects for Lunacera in figure 4.15 and
figure 4.17 are the effects calculated using the logarithms of the outcomes. Attachment 16
gives an overview of the transformed and untransformed effects for the Lunacera design.
Because of the logarithmic transformation, it is impossible to evaluate and to compare the
relevance of the size of the effects with the other designs. Therefore, the error bars of the
transformed data were used to assess the significance, but in order to compare the
magnitudes, the effects were transformed back using the inverse log.
4.3.1.1. PEG 4000
The amount of PEG 4000 added has a negative effect on the friability of the tablets.
The more binder is added during granulation, the more free binder will be available at the
surface of the granules for deformation, resulting in stronger interparticular bonds. The
interaction between the throughput and the temperature, which can be seen in figure 4.15,
is also significant. This interaction shows that when operating at a low temperature, an
increase in throughput leads to more friable tablets. Following scenario might offer an
explanation. At a low temperature, distribution of the binder over the particles is impeded
and at a high throughput, the residence time inside the barrel is reduced, as documented by
Dhenge et al. These two effects combined might lead to less binding and hence more friable
granules. The raw data from the runs executed at low temperature and high throughput
showed that the granules with 5 % PEG 4000 exerted a high level of friability (above 40 %),
whereas the friability of the granules with 20 % PEG 4000 amounts to about 15 %. These first
two runs, with a granule friability of over 40 %, coincide with the runs that displayed capping.
So one may assume that during compression, fragmentation of the granules occurs resulting
in an abundance of particles with a mean size below 150 µm (fines), resulting in an impeded
evacuation of air and capping. (Dhenge et al., 2011) (Handbook of Pharmaceutical Excipients,
2009)
42
Figure 4.15. Interaction plot of throughput and temperature for PEG 4000 (left) and Lunacera (right)
4.3.1.2. Stearic acid
The tablets obtained from the stearic acid design all have an acceptable friability,
which is lower than 1 %. One should, however, be ascertained that a lower friability is
obtained when using granules which are produced at a high screw speed and when using
low amount of stearic acid, so altering these parameters may result in an increase of tablet
friability. This is shown in figure 4.16.
Figure 4.16. Interaction plot of screw speed and binder concentration for stearic acid
4.3.1.3. Lunacera
For Lunacera, the concentration used during granulation had a negative effect on the
friability of the tablets. The higher the amount of Lunacera used, the less friable the tablets
become as they become plastically deformable at high concentrations of Lunacera (see
section 4.3.2). The Lunacera design exhibits a significant interaction between the throughput
43
and the temperature, shown in figure 4.15, where at a low operating temperature, the
increase in throughput will result In a decrease of tablet friability, whereas at high
temperatures a small increase in tablet friability is detected when the throughput is
increased.
Figure 4.17. Interaction plot of temperature and binder concentration for Lunacera
Another interaction, depicted in figure 4.17, was found to have a significant effect on
the friability of the tablets from the Lunacera design, namely between the temperature and
the binder concentration. When low amounts of Lunacera were used, an increase in
temperature results in a decrease of tablet friability. This is because at low concentrations,
an increase in temperature will decrease the viscosity of Lunacera and hence it will promote
a better distribution over the individual drug particles. This improved binder distribution
increases the free amount of binder at the surface of the particles which is free for plastic
deformation during compression. Since plastic deformation has a positive effect on the
strength interparticular bridges (Dhenge et al., 2011), this will result in stronger tablets.
When a high concentration of binder was used, the same increase in temperature results in
a slight increase in tablet friability. This slight increase, however, should not be considered
relevant as the tablets with high concentrations of Lunacera exhibit sufficiently low friability
(average below 0,20 %, according to the raw data). Overall, one can see that an increase in
binder concentration will result in a less friable tablet, which is consistent with the main
effect.
44
Figure 4.18. Effect plots for friability of tablets
4.3.2. Influence on tensile strength
When comparing the tensile strength of the tablets (table 4.6), it was apparent that
the tablets with the highest tensile strength as well as the tablets with the highest average
tensile strength were obtained via the Soluplus design, whereas the tablets with the lowest
average tensile strength were obtained when Lunacera was used. PEG and Stearic acid
yielded tablets with an intermediate average tensile strength. Attachment 18 presents an
overview of the raw data analysis performed on the data for the tablet tensile strength for
all experimental designs. For the Lunacera design, the RNP plot showed that all points (1 to
16) were on a straight line on the diagonal, except for the three center points.
Minimum Maximum Average
PEG 4000 1,219 2,665 1,975
Soluplus 1,414 3,329 2,592
Stearic acid 1,497 2,208 1,773
Lunacera 0,010 1,468 1,145
Table 4.6. Tensile strength in MPa per design
4.3.2.1. PEG 4000
The amount of PEG 4000 used during granulation had a negative effect on the tensile
strength, thus yielding weaker tablets as more binder is used. An increase in PEG 4000 used
-2
-1,5
-1
-0,5
0
0,5
1
1,5
Throughput Screw Speed Temperature % Binder
% F
riab
ility
Main factor
Friability tablets
PEG4000
Soluplus
Stearic acid
Lunacera
45
during granulation yields less friable granules (see 4.2.1.1), resulting in less granular
fragmentation and a subsequently lower tensile strength due to a lower amount of contact
points (Mattsson, 2000). Following this line or reasoning, this might also be explained by the
observations made by McKenna et al. and Okor et al., that an increase in granule size may
lead to a reduction in tensile strength. Increasing the PEG 4000 concentration does not only
increase the yield, as reported in section 4.2.2.1, but it also leads to an increase in the
particle size within the yield fraction. The fraction of the yield between 710 µm and 1,4 mm
underwent a relative increase of about 30 % when 20 % PEG 4000 was used compared to
5 % binder. McKenna et al. ascribed the reduction in mechanical strength to the decrease in
available surface area when particles become bigger, which reduces intergranular attractions.
(Mattsson, 2000) (McKenna et al., 1982) (Okor et al., 1998)
Furthermore, the interaction between the amount of binder and the screw speed
was found to be significant. This interaction is represented graphically in figure 4.21. As
increasing amounts of binder are used during granulation whilst operating at a low screw
speed, a decrease in tensile strength is noticeable. This may be attributable to the decrease
in granular friability when increasing the screw speed at low concentrations of PEG 4000
(see 4.2.1.6), reducing the fragmentation and the amount of contact points as mentioned
above. When operating at high screw speeds the amount of binder added has only a minor
positive effect on the strength of the tablets. It is also apparent that operating at a high
screw speed yields weaker tablets compared to operating at a low screw speed, up until
approximately 18 % PEG 4000 is used. (Mattsson, 2000)
4.3.2.2. Soluplus
The throughput and the temperature both have a positive effect on the tensile
strength of the tablets made in the Soluplus design, whilst the screw speed exerts a negative
effect. The effect of the temperature might be explained since at higher temperatures,
Soluplus softens and the distribution over the particle surface facilitated. This leads to more
free binder at the surface of the resulting granules, which in turn makes more binder
available for bridge formation during compression. The opposite effect of the throughput
and the screw speed might be indicative that the degree of screw fill plays an important role
in the tensile strength. At low throughput and high screw speed, the screws aren’t
46
adequately filled and for Soluplus, as seen under section 4.2.2.2, this results in a mono-
modal distribution of the granules. This mono-modal distribution appears to have a negative
influence on the tablet hardness. This can be explained, since most particles have the same
size, no smaller particles are available to fill the pores, which results in a higher tablet
porosity. Djuric reported in 2008 that the tensile strength is inversely proportional to the
tablet porosity. (Djuric, 2008)
Figure 4.19. Interaction plot of screw speed and binder concentration for Soluplus
The interaction between the throughput and the screw speed (shown in figure 4.19)
is also significant. An increase in screw speed will result in a decrease of tensile strength, as
implied by the main effect. However, at a high throughput this decrease is far less significant
than when operating at a low throughput, because of the higher degree of screw fill.
4.3.2.3. Stearic acid
For stearic acid, an increase in screw speed is accompanied by an increase in tensile
strength. The screw speed is also found in the interaction with the amount of stearic acid
used during granulation. The interaction confirms that, as the screw speed is raised, the
tensile strength increases as well. However, as more binder is used, the effect of the screw
speed diminishes up to the point that an increase of screw speed only faintly increases
tensile strength. The interaction can be seen in figure 4.21.
47
4.3.2.4. Lunacera
In the Lunacera design a decrease of tensile strength was noticeable in case of an
increasing amount of binder added to the powder mixture. However, it should be noted that,
when high amounts of Lunacera were used, the tablets didn’t exhibit diametrical breakage,
as the tablets as a whole became plastically deformable and thus were awarded a value of
0,01 MPa for tensile strength, which has a major influence on the effect. Therefore, the data
were analysed using only the values obtained when using 5 % Lunacera, in order to exclude
the influence of the amount of binder.
At first glance, no factors had a significant effect. However, after logarithmically
transforming the data, is was apparent that the throughput and the temperature had a
positive influence on the tensile strength, as well as their interaction. As can be seen in
figure 4.20, increasing the temperature at a low throughput increases the tensile strength of
the tablets with 5 % binder. At a higher level of throughput, the tensile strength only
increases slightly with increasing temperature. Another interaction was also found to be
significant when analysing the data from the runs with 5 % Lunacera, namely the interaction
between the throughput and screw speed. The interaction (attachment 19) shows us that an
increase in throughput will always result in an increase in tensile strength, which is also
observed through the main effect. The effect of the screw speed, however, is dependent on
the level of the throughput. At a high throughput, an increasing screw speed results in
slightly stronger tablets, whilst the same increase will result in weaker tablets when
operating at a low throughput. This combination of low throughput and high screw speed
leads to suboptimal filling of the screw, which in turn yields less dense granules, which are
more prone to breaking. Lastly, the interaction between the screw speed and the
temperature (attachment 20) shows that at high temperatures, the screw speed has little
effect. At low temperatures, there is a significant decrease in tensile strength when the
screw speed is raised.
48
Figure 4.20. Interaction plot throughput and temperature for Lunacera
4.3.2.5. PEG 4000-Stearic acid
For both PEG and stearic acid, only the interaction between the screw speed and the
amount of binder used, shown in figure 4.21, has a significant effect on the tensile strength.
The interaction, however, isn’t identical for both designs but it’s rather opposite. For PEG,
operating at a higher screw speed will induce a decrease of tensile strength at low binder
concentrations and an increase at high binder concentrations, whereas an increase will occur
at low concentrations of stearic acid and virtually no change in tensile strength will ensue at
high binder levels.
Figure 4.21. Interaction plot of screw speed and binder concentration for PEG 4000 (left)
and stearic acid (right)
49
4.3.2.6. Soluplus-Lunacera
When Lunacera is used in low concentrations, the throughput and the temperature
both have a positive effect on the tensile strength of the resulting tablets, as is the case
when Soluplus is used. The interaction between the throughput and the screw speed is also
significant for both binders. At a low throughput, an increase in screw speed leads to weaker
tablets for both binders. At a high throughput however, the same increase results in a
diminution of tensile strength in the Soluplus design while it leads to stronger tablets when
5 % Lunacera was used.
4.3.2.7. Crystalline-Amorphous
When using crystalline binders, one should be aware of the interaction between the
screw speed and the amount of binder used, since the effect of the interaction is dependent
on which binder was used. The tensile strength of tablets made with granules comprising an
amorphous binder is mainly influenced by the operating temperature and the throughput
during granulation. A higher temperature or a higher throughput leads to stronger tablets.
Also note the similar effect of the binder concentration on the tensile strength when using a
binder with semi-crystalline properties.
Figure 4.22. Effect plots for tensile strength
-2
-1,5
-1
-0,5
0
0,5
1
1,5
Throughput Screw Speed Temperature % Binder
MP
a
Main factor
Tensile strength
PEG4000
Soluplus
Stearic acid
Lunacera
50
4.3.3. Influence on dissolution
Using granules with a hydrophilic binder will result in a tablet with immediate-release
properties, whereas where a hydrophobic binder was used, a sustained-release dosage form
was obtained. Consequently, since the dissolution is analysed via the release of the drug
after a certain amount of time, different release times were used for the hydrophilic and
hydrophobic binders. For the hydrophilic binders PEG 4000 and Soluplus, dissolution was
evaluated via the amount of drug released after 5 minutes, for the hydrophobic binders
stearic acid and Lunacera the dissolution time was 1 hour. Table 4.7 gives an overview of the
maximum and minimum amounts of drug released for each design, as well as an average
release. Attachment 23 gives an overview of the raw data analysis performed. For the
Lunacera design, the RNP plot showed that all points were on a straight line on the diagonal,
except for the three center points.
Minimum Maximum Average
PEG 4000 61,36 84,21 72,39
Soluplus 33,26 78,88 63,16
Stearic acid 51,29 92,38 77,12
Lunacera 0,01 94,97 53,15
Table 4.7. Dissolution in percentage per design
Evaluation of the raw data shows that tablets produced with PEG 4000 have a higher
release after 5 minutes compared to tablets containing Soluplus, both at a low concentration
as well as at a high concentration of binder. This can be attributed to the higher tablet
hardness of the tablets containing Soluplus, as hardness has a negative influence on the drug
release rate, which was also documented by Saravanan et al. The dissolution of the drug
from the tablets with hydrophilic binder occurred faster than the drug release from the
commercial immediate-release formulation Lopresor®, releasing approximately 60-70 % of
the drug after 5 minutes, with the complete dissolution occurring within 10 minutes,
whereas the drug release after 5 minutes for Lopresor® was about 22 % according to Leigh et
al., with a complete dissolution occurring within 30 minutes. For the hydrophobic binders,
Lunacera showed a slightly faster release at 5 % binder concentration when compared to
51
stearic acid. However at high binder concentrations, the tablets with stearic acid released
the drug much faster than the tablets containing high amounts of Lunacera.
(Leigh et al., 2013) (Saravanan et al., 2002)
4.3.3.1. Common effect
Regardless of the binder used during granulation, increasing the binder concentration
will result in tablets with a lower dissolution rate. However, even though the effects are
similar, they are not equal in terms of magnitude, as can be seen in figure 4.25. For stearic
acid, the increase in binder concentration results in an decrease of dissolution of the drug,
comparable to PEG 4000 and Soluplus. However, the effect of an increase in binder
concentration is far greater for Lunacera than for the other binders. This is attributable to
the fact that the tablets containing high amounts of Lunacera do not dissolve (unlike PEG
4000 and Soluplus) nor do they disintegrate (opposed to the tablets containing stearic acid).
Instead, they remain relatively intact, preventing water from reaching the core of the tablet
and dissolving the drug. This can be seen in figure 4.23.
Figure 4.23. Disintegrated tablet containing stearic acid (left),
intact tablets containing Lunacera (right)
4.3.3.2. PEG 4000
An increase in the processing temperature positively influences the dissolution, as an
increase above the melting temperature of PEG 4000 will liquefy the binder, facilitating the
52
formation of a solid solution with metoprolol. Consequently, as the binder dissolves,
metoprolol will be released as well, explaining the higher amount of drug dissolved after 5
minutes.
4.3.3.3. Soluplus
It is noteworthy that the tablets from runs 3, 11 and 15, the runs coinciding with a
low degree of screw fill and thus exhibiting a mono-modal distribution, all have considerably
lower dissolution rates. Table 4.14 gives an overview of the drug release after 5 minutes for
each run, as well as the average release for tablets with 5 % and 15 % Soluplus. From this,
one can conclude that a mono-modal granular size distribution results in a slower release
when Soluplus is used as a binder.
Run 3 Run 11 Run 15
Release 55,55% 40,77% 33,26%
Average release 70,17% 54,31% 54,31%
Table 4.14. Dissolution after 5 minutes for runs with mono-modal distribution
4.3.3.4. Stearic Acid
For stearic acid, increasing the granulation temperature will result in tablets with a
higher dissolution rate. The interaction between the temperature and the amount of binder
added was also significant for stearic acid. This interaction, shown in figure 4.23, shows that
the negative influence of the binder concentration is much higher at low temperatures
compared to high temperatures. This may be due to the formation of a solid solution of
metoprolol and the molten stearic acid at high temperatures, as reported by Vervaeck et al.
This solid dispersion improves the dissolubility of the drugs resulting from the occurrence in
amorphous form. (Vervaeck et al., 2013)
4.3.3.5. Crystalline-Amorphous
The crystalline binders have two mutual effects influencing the release of the drug
from the tablet, being the binder concentration and the temperature, due to the formation
of a solid solution, whilst the drug release from a tablet made with an amorphous binder is
only influenced by the binder concentration used to manufacture the granules.
53
Figure 4.24. Interaction plot of throughput and temperature for stearic acid
Figure 4.25. Effect plots for dissolution
-120
-100
-80
-60
-40
-20
0
20
40
Throughput Screw Speed Temperature % Binder
% R
ele
ase
Main factor
Dissolution
PEG4000
Soluplus
Stearic acid
Lunacera
54
5. Conclusion
Four full factorial screening designs, one for each binder (PEG 4000, Soluplus, stearic
acid and Lunacera) were drawn up, executed and analysed in order to identify which process
parameters (throughput, screw speed, temperature and binder concentration) are critical
during granulation using a twin-screw extruder and what their effect is on the different
responses (granular friability, particle size distribution, flowability, true density, tablet
friability, tablet tensile strength and dissolution).
Of the four process parameters, the binder concentration was found to be influential
for nearly every response of every design. An increase in the amount of binder used during
granulation will generally yield less friable, bigger granules whilst reducing the amount of
fines, resulting in particles with better flowing properties. The true density of the particles,
however, was only influenced when using a hydrophobic binder. Tablets with a higher binder
content were found to have lower dissolution rates compared to tablets containing only 5 %
binder. Moreover, the binder concentration also had a negative influence on the tensile
strength and the friability of the tablets, although this effect was only observed for the semi-
crystalline binders. Finally, it should be noted that the processability of the hydrophobic
binders is much higher compared to the hydrophilic binders, which explains why higher
amounts of stearic acid and Lunacera were used during granulation. This also accounts for
the fact that the effects of the binder concentration observed in the designs using a
hydrophobic binder are of a greater magnitude compared to the other two designs.
The throughput appears to mainly influence the granular properties when a
hydrophilic binder is used. Although the effect is usually similar, it was found that an
increase in throughput resulted in a slightly higher yield when PEG 4000 was used, opposed
to a marked drop in yield of approximately 20 % when Soluplus was used, due to the
formation of oversized particles.
The temperature seemed to mainly have an impact on the properties of the granules
obtained when using stearic acid as the binder, although it does exhibit a positive effect on
the dissolution rate of both PEG 4000 and stearic acid.
55
Finally, the degree of screw fill, a composite parameter comprising both the
throughput and the screw speed, had an interesting effect on the granular characteristics
and the tablet properties when Soluplus was used. When granulating at a high screw speed
whilst feeding at a low throughput, the screws inside the barrel are inadequately filled. This
resulted in a mono-modal particle size distribution, which had a detrimental effect on the
properties of both the granules and the tablets. Although the mono-modal distribution was
exclusively observed in the Soluplus design, the degree of screw fill was also found to have
an effect on the other hydrophilic binder, PEG 4000. A higher filling of the screws resulted in
a higher densification inside the barrel, leading to less fines and better flowing granules.
In this thesis, it has been demonstrated that, even though binders with similar
characteristics demonstrate certain similarities, each binder influences the responses in a
different way. One way of enabling the prediction of the outcome of a twin-screw melt
granulation process when using a certain binder is through the establishment of an extensive
database comprising all common and less commonly used binders and the associated effects
of the process parameters.
56
6. BIBLIOGRAPHY
Abberger, T.; Seo, A.; Schaefer, T. (2002). The effect of droplet size and powder particle size
on the mechanisms of nucleation and growth in fluid bed melt agglomeration. Int. J.
Pharm., 249, 185-197
Agrawal, R.; Naveen, Y. (2011). Pharmaceutical Processing – A Review on Wet Granulation
Technology. IJPFR, 1, 56-83
BASF. (2010). Soluplus®: technical information [pdf]. Available at: http://www.innovate-
excipients.basf.com/Statements/Technical%20Informations/EN/Pharma%20Solutions
/03_090801e_Soluplus.pdf.
Dhenge, R.M.; Fyles, R.S.; Cartwright, J.J.; Doughty, D.G.; Hounslow, M.J.; Salman, A.D.
(2010). Twin-screw wet granulation: Granule properties. Chem. Eng. J., 164, 322-329
Dhenge, R.M.; Cartwright, J.J.; Doughty, D.G.; Hounslow, M.J.; Salman, A.D. (2011). Twin-
screw wet granulation: Effect of powder feed rate. Adv. Powder Technol., 22, 162-166
Dhirendra, A.; Lewis, S.; Udupa, N.; Atin, K. (2009). Solid dispersions: a review. Pak. J. Pharm.
Sci. ,22, 234-246
Djuric, D. (2008). Continuous granulation with a twin-screw extruder. PhD thesis, University
of Dusseldorf, Germany
Djuric, D.; Van Melkebeke, B.; Kleinebudde, P.; Remon, J.P.; Vervaet, C. (2009). Comparison
of two twin-screw extruders for continuous granulation. Eur. J. Pharm. Biopharm., 71,
155-160
Djuric, D.; Kleinebudde, P. (2010). Continuous granulation with a twin-screw extruder:
impact of material throughput. Pharm. Dev. Technol., 15, 518-525
Djuric, D. (2011). Soluplus®. In: Solubility enhancement with BASF pharma polymers, Reintjes,
T. (Ed.), BASF, Ludwigshafen, Germany, pp. 67-72
Djuric, D.; Kolter, K. (2011). Melt granulation with a twin-screw extruder using Soluplus.
Poster, AAPS Annual Meeting, Washington.
57
Eriksson, L.; Johansson, E.; Kettaneh-Wold, N.; Wikström, C.; Wold, S. (2008). Design of
Experiments: Principles and Applications, 3th edition, MKS Umetrics UB, Umeå,
Sweden
European pharmacopeia 5.0 (2005). European Directorate for the Quality of Medicines &
Healthcare, Counsil of Europe, Strasbourg, France
European pharmacopeia 7.0 (2011). European Directorate for the Quality of Medicines &
Healthcare, Counsil of Europe, Strasbourg, France
Evrard, B.; Amighi, K.; Beten, D.; Delattre, L.; Moës, A.J. (1999). Influence of Melting and
Rheological Properties of Fatty Binders on the Melt Granulation Process in a High-
Shear Mixer. Drug. Dev. Ind. Pharm., 25, 1177-1184
Gamlen, M.J.; Eardley, C. (1986). Continuous extrusion using a Baker Perkins MP50
(Multipurpose) extruder. Drug. Dev. Int. Pharm., 12, 1701-1713
Gokhale, R.; Sun, Y.; Shukla, A.J. (2005). High shear granulation. In: Handbook of
Pharmaceutical Granulation Technology, 2nd edition, Parikh, D. (Ed.), Taylor & Francis,
Florida, USA, pp. 191-228
Guidechem. (2012) Metoprolol. Available at:
http://www.guidechem.com/dictionary/en/37350-58-6.html
Handbook of Pharmaceutical Excipients, 6th edition (2009). Rowe, R.C.; Sheskey, P.J.; Owen,
S.C. (Eds), Pharmaceutical Press, London, UK
Iveson, S. M.; Litster, J. D.; Hapgood, K.; Ennis, B. J. (2001). Nucleation, growth and breakage
phenomena in agitated wet granulation processes: a review. Powder Technol., 117,
3-39
Keleb, E.I.; Vermeire, A.; Vervaet, C.; Remon, J.P. (2002). Continuous twin-screw extrusion
for the wet granulation of lactose. Int. J. Pharm., 239, 69-80
Keleb, E.I.; Vermeire, A.; Vervaet, C.; Remon, J.P. (2004a). Twin-screw granulation as a simple
and efficient tool for continuous wet granulation. Int. J. Pharm., 273, 183-194
58
Keleb, E.I.; Vermeire, A.; Vervaet, C.; Remon, J.P. (2004b). Extrusion granulation and high
shear granulation of different grades of lactose and highly dosed drugs: a
comparative study. Drug. Dev. Ind. Pharm., 30, 679-691
Kleinebudde, P.; Lindner, H. (1993). Experiments with an instrumented twin-screw extruder
using a single-step granulation/extrusion process. Int. J. Pharm., 94, 49-58
Kleinebudde, P. (2004). Roll compaction/dry granulation: pharmaceutical applications. Eur. J.
Pharm. Biopharm., 58, 317-326
Kolter, K.; Karl, M.; Nalawade, S.; Rottmann, N. (2011). Introduction to hot-melt extrusion for
pharmaceuticals. In: Hot-melt extrusion with BASF pharma polymers, 2nd edition,
BASF, Ludwigshafen, Germany, pp. 8-23
Kowalski, J.; Kalb, O.; Joshi, Y.M.; Serajuddin, A.T.M. (2009). Application of melt granulation
technology to enhance stability of a moisture sensitive immediate-release drug
product. Int. J. Pharm., 381, 56-61
Lakshman, J.P.; Kowalski, J.; Vasanthavada, M; Tong, W.Q.; Joshi, Y.M.; Serajuddin, A.T.M.
(2011). Application of melt granulation technology to enhance tableting properties of
poorly compactible high-dose drugs. J. Pharm. Sci., 100, 1553 – 1565
Lazic, Z.R. (2004). Design of Experiments in Chemical Engineering, Wiley-VCH, Weinheim,
Germany
Leigh, M.; Kloefer, B.; Schaich, M. (2013). Comparison of the solubility and dissolution of
drugs in fasted-state biorelevant media (FaSSIF and FaSSIF-V2). Dissolution
Technologies, 20, 44-55
Lindberg, N.O.: Tufvesson, C.; Olbjer, L. (1978). Extrusion of an effervescent granulation with
a twin-screw extruder, Baker Perkins MPF 50 D. Drug. Dev. Ind. Pharm., 13, 1891-
1913
Martin, C. (2013). Twin-Screw Extrusion for Pharmaceutical Processes. In: Melt Extrusion:
Materials, Technology and Drug Product Design, Vol. 9, Repka, M.A., Langly, N.,
DiNunzio, J. (Eds.), Springer, Berlin, Germany, pp. 47-79
59
Martindale: the complete drug reference, 36th edition (2009). Sweetman, S.C. (ED.),
Pharmaceutical Press, London, UK
Mattsson, S. (2000). Pharmaceutical Binders and Their Function in Directly Compressed
Tablets. PhD thesis, Uppsala University, Sweden
McKenna, A.; McCafferty, D.F. (1982). Effect of particle size on the compaction mechanism
and tensile strength of tablets. J. Pharm. Pharmacol., 34, 347-351
Miller R.W. (2005). Roller Compaction Technology. In: Handbook of Pharmaceutical
Granulation Technology, 2nd edition, Parikh, D. (Ed.), Taylor & Francis, Florida, USA,
pp. 159-190
Mollan, M. (2003). Historical overview. In: Pharmaceutical Extrusion Technology. Ghebre-
Sellasie, I., Martin, C. (Eds.), Marcel Dekker, New York, USA, pp. 1-18
Mu, B.; Thompson, M.R. (2012). Examining the mechanics of granulation with a hot melt
binder in a twin-screw extruder. Chem. Eng. Sci., 81, 46-56
NIST/SEMATECH. (2013). e-Handbook of Statistical Methods. Available at:
http://www.itl.nist.gov/div898/handbook/
Okor, R.S., Eichie, F.E., Ngwa, C.N. (1998). Correlation between tablet mechanical strength
and brittle fracture tendency. Pharm. Pharmacol. Commun., 4, 511-513
Patel, A.; Sahu, D.; Dashora, A.; Garg, R.; Agraval, P.; Patel, P.; Patel, P.; Patel, G. (2013). A
review of hot melt extrusion technique. IJIRSET, 2, 2194-2198
Pitt, K.G.; Heasley, M.G. (2013). Determination of the tensile strength of elongated tablets.
Powder Technol., 238, 169-175
Plumb, K. (2005). Continuous processing in the pharmaceutical industry: Changing the mind-
set. Chem. Eng. Sci., 83, 730-738
Remon, J.P.; Vervaet, C. (2011). Farmaceutische technologie. Hoofdstuk 2:
Agglomeratieprocessen, Academia Press, Ghent, Belgium, pp. 15-87
Saravanan, M.; Nataraj, K.S.; Ganesh, K.S. (2002). The effect of tablet formulation and
hardness on in vitro release of cephalexin from Eudragit L100 based extended release
tablets. Biol. Pharm. Bull., 25, 541-542
60
Schaefer, T.; Mathiesen, C. (1996). Melt pelletization in a high shear mixer. VIII. Effects of
binder viscosity. Int. J. Pharm., 139, 125-138
Schaefer, T. (2001). Growth mechanisms in melt agglomeration in high shear mixers. Powder
Technol., 117, 68-82
Scott A.C.; Hounslow, M.J.; Instone, T. (2000). Direct evidence of heterogeneity during high-
shear granulation. Powder Technol., 113, 205–213
Serajuddin, A.T.M. (2011). Melt extrusion and melt granulation processes in development of
drug products. St. John’s University, Queens, New York, USA
United States Pharmacopeia, 32th edition (2008). United States Pharmacopeial Convention,
Maryland, USA
Van Melkebeke, B.; Vermeulen, B.; Vervaet, C.; Remon, J. P. (2006). Melt granulation using a
twin-screw extruder: A case study. Int. J. Pharm., 326, 89-93
Van Melkebeke, B.; Vervaet, C.; Remon, J.P. (2008). Validation of a continuous granulation
process using a twin-screw extruder. Int. J. Pharm., 356, 224-230
Vasanthavada, M.; Wang, Y.; Haefele, T.; Lakshman, J.P.; Mone, M.; Tong, W.Q.; Joshi, Y.M.;
Serajuddin, A.T.M. (2011). Application of melt granulation technology using twin-
screw extruder in development of high-dose modified-release tablet formulation. Int.
J. Pharm., 100, 1923-1934
Vercruysse, J.; Córdoba Díaz, D.; Peeters, E.; Fonteyne, M.; Delaet, U.; Van Assche, I.; De Beer,
T.; Remon, J. P.; Vervaet, C. (2012). Continuous twin-screw granulation: influence of
process variables on granule and tablet quality. Eur. J. Pharm. Biopharm., 82, 205-211
Vervaeck, A.; Saerens, L.; De Geest, B.G.; De Beer, T.; Carleer, R.; Adriaensens, P.; Remon, J.P.;
Vervaet, C. (2013). Prilling of fatty acids as a continuous process for the development
of controlled release multiparticulate dosage forms. Eur. J. Pharm. Biopharm., 85,
587-596
Vervaet, C.; Remon, J.P. (2005). Continuous granulation in the pharmaceutical industry.
Chem. Eng. Sci., 60, 3949-3957
61
Vervaet, C.; Remon, J.P. (2009). Melt Granulation. In: Handbook of Pharmaceutical
Granulation Technology, 3rd edition, Parikh, D. (Ed.), Informa Healthcare, New York,
USA, pp. 435-448
Vilhelmsen, T.; Schaefer, T. (2005). Agglomerate formation and growth mechanisms during
melt agglomeration in a rotary processor. Int. J. Pharm., 304, 152-164
Walker, G.M.; Andrews, G.; Jones, D. (2006). Effect of process parameters on the melt
granulation of pharmaceutical powders. Powder Technol., 165, 161-166
Wold, S. (1995). PLS for multivariate linear modelling. In: Chemometric methods in Molecular
Design, van de Waterbeemd, H. (Ed.), VCH, Weinheim, Germany, pp. 195-218
Yadav, V.B.; Deshpande, O.A. (2009). Improvement in physicochemical properties of
indomethacin by melt granulation technique. Int. J. ChemTech, 4, 1312-1317
Attachments
Granule friability
PEG 4000 Soluplus Stearic acid Lunacera
Condition number 1,1374 1,0897 1,8973 1,0897
CP variability middle, smaller bottom, smaller bottom, smaller middle, smaller
Transformation linear linear linear linear
R2 0,919 0,947 0,893 0,925
Q2 0,394 0,404 0,596 0,682
Model validity 0,741 0,644 0,197 -0,200
Reproducibility 0,900 0,985 0,987 0,999
RNP: outliers none 12 none none
RNP: plot straight line straight line straight line straight line
Deleted none 12 none none
Attachment 1. Overview data granule friability
Attachment 2. Interaction plot of throughput and temperature for PEG 4000
Attachment 3. Interaction plot of throughput and screw speed for Soluplus
Attachment 4. Interaction effect plot for friability of granules
-15
-10
-5
0
5
10
15
20
Thr*
Scr
Thr*
Tem
p
Thr*
%B
Scr*
Tem
p
Scr*
%B
Tem
p*
%B
% F
riab
ility
Factor-interaction
Friability granules
PEG4000
Soluplus
Stearic acid
Lunacera
Particle size distribution
Attachment 5. Loadings plot for PEG 4000
Attachment 6. Loadings plot for Soluplus
Attachment 7. Loadings plot for Stearic acid
Attachment 8. Loadings plot for Lunacera
Attachment 9. Interaction plots of throughput and binder concentration for PEG 4000
Flowability
PEG 4000 Soluplus Stearic acid Lunacera
Condition number 1,1374 1,0897 1,8973 1,0897
CP variability middle, smaller bottom, smaller middle, smaller middle, smaller
Transformation linear linear linear linear
R2 0,788 0,759 0,900 0,910
Q2 -0,892 -0,181 0,518 0,482
Model validity 0,202 0,419 0,948 0,022
Reproducibility 0,973 0,990 0,777 0,996
RNP: outliers none none none none
RNP: plot straight line straight line straight line straight line
Deleted none none none none
Attachment 10. Overview data flowability
Attachment 11. Interaction effect plot for flowability
True density
PEG 4000 Soluplus Stearic acid Lunacera
Condition number 1,1374 1,0897 1,8973 1,0897
CP variability middle, smaller bottom, smaller middle, smaller middle, smaller
Transformation linear linear linear linear
R2 0,798 0,738 0,973 0,998
Q2 -1,293 0,074 0,886 0,995
Model validity 0,247 0,678 0,273 0,864
Reproducibility 0,966 0,910 0,996 0,997
RNP: outliers 14 none none none
RNP: plot straight line straight line straight line straight line
Deleted 14 none none none
Attachment 12. Overview data true density
-0,2
-0,15
-0,1
-0,05
0
0,05
0,1
Thr*
Scr
Thr*
Tem
p
Thr*
%B
Scr*
Tem
p
Scr*
%B
Tem
p*
%B
Hau
sne
r ra
tio
Factor-interaction
Flowability granules
PEG4000
Soluplus
Stearic acid
Lunacera
Attachment 13. Effect plot for true density with 5 % binder
Attachment 14. Interaction effect plot for true density
-0,0250
-0,0200
-0,0150
-0,0100
-0,0050
0,0000
0,0050
Throughput Screwspeed Temperature
Tru
e d
en
sity
(kg
/l)
Factor
True density 5 %
PEG 4000
Soluplus
Stearic acid
Lunacera
-0,07
-0,06
-0,05
-0,04
-0,03
-0,02
-0,01
0
0,01
0,02
0,03
0,04
Thr*
Scr
Thr*
Tem
p
Thr*
%B
Scr*
Tem
p
Scr*
%B
Tem
p*
%B
Tru
e d
en
sity
(kg
/l)
Factor-interaction
True density
PEG4000
Soluplus
Stearic acid
Lunacera
Tablet friability
PEG 4000 Soluplus Stearic acid Lunacera
Condition number 1,1374 1,0897 1,8973 1,0897
CP variability middle, smaller middle, smaller middle, smaller bottom, smaller
Transformation linear linear linear logarithmic
R2 0,749 0,601 0,735 0,890
Q2 -1,375 -2,527 -0,468 -0,047
Model validity 0,148 0,610 0,402 -0,102
Reproducibility 0,975 0,922 0,925 0,996
RNP: outliers none none none none
RNP: plot straight line straight line straight line straight line
Deleted none none none none
Attachment 15. Overview data tablet friability
Attachment 6.16. Effect values for transformed and untransformed data from the Lunacera design
-1,2
-1
-0,8
-0,6
-0,4
-0,2
0
0,2
0,4
0,6
0,8
1
Thro
ugh
pu
t
Scre
w S
pee
d
Tem
pe
ratu
re
% B
ind
er
Thr*
Scr
Thr*
Tem
p
Thr*
%B
Scr*
Tem
p
Scr*
%B
Tem
p*
%B
% F
riab
ility
Factor(-interaction)
Transformed vs untransformed
Untransformed
Transformed
Attachment 6.17. Interaction effect plot for true density
Tensile strength
PEG 4000 Soluplus Stearic acid Lunacera
Condition number 1,1374 1,0897 1,8973 1,0897
CP variability middle, smaller middle, smaller top, smaller bottom, smaller
Transformation linear linear linear linear
R2 0,716 0,858 0,754 0,862
Q2 -1,331 -0,057 -0,220 0,552
Model validity 0,103 0,508 0,035 n/a
Reproducibility 0,976 0,988 0,984 1,000
RNP: outliers none none none none
RNP: plot straight line straight line straight line straight line, ex CP
Deleted none none none none
Attachment 18. Overview data tensile strength
-1,5
-1
-0,5
0
0,5
1
1,5Th
r*Sc
r
Thr*
Tem
p
Thr*
%B
Scr*
Tem
p
Scr*
%B
Tem
p*
%B
% F
riab
ility
Factor-interaction
Friability tablets
PEG4000
Soluplus
Stearic acid
Lunacera
Attachment 19. Interaction plot of throughput and screw speed for Lunacera 5 percent
Attachment 20. Interaction plot of screw speed and temperature for Lunacera 5 percent
Attachment 21. Effect values for transformed and untransformed data from
the Lunacera design with 5 % binder
Attachment 22. Interaction effect plot for true density
-0,3
-0,2
-0,1
0
0,1
0,2
0,3
0,4
Thro
ugh
pu
t
Scre
w S
pee
d
Tem
pe
ratu
re
Thr*
Scr
Thr*
Tem
p
Scr*
Tem
p
Ten
sile
str
en
gth
(M
Pa)
Factor(-interaction)
Transformed vs untransformed
Untransformed
Transformed
-0,8
-0,6
-0,4
-0,2
0
0,2
0,4
0,6
0,8
1
Thr*
Scr
Thr*
Tem
p
Thr*
%B
Scr*
Tem
p
Scr*
%B
Tem
p*
%B
MP
a
Factor-interaction
Tensile strength
PEG4000
Soluplus
Stearic acid
Lunacera
Dissolution
PEG 4000 Soluplus Stearic acid Lunacera
Condition number 1,1374 1,0897 1,8973 1,0897
CP variability middle, smaller middle, smaller top, smaller bottom, smaller
Transformation linear linear linear linear
R2 0,904 0,733 0,932 0,964
Q2 0,134 -1,288 0,841 0,914
Model validity 0,575 0,357 0,999 0,541
Reproducibility 0,943 0,993 0,487 0,982
RNP: outliers none none 16 none
RNP: plot straight line straight line straight line straight line, ex CP
Deleted none none 16 none
Attachment 23. Overview data dissolution
Attachment 24. Interaction effect plot for dissolution
-20
-15
-10
-5
0
5
10
15
20
25
Thr*
Scr
Thr*
Tem
p
Thr*
%B
Scr*
Tem
p
Scr*
%B
Tem
p*
%B
% R
ele
ase
Factor-interaction
Dissolution
PEG4000
Soluplus
Stearic acid
Lunacera