GHENT UNIVERSITY FACULTY OF PHARMACEUTICAL SCIENCES

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


4.2.3. 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


4.2.4. 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.


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 %:


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)


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.


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


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


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.


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.


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).


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.


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.


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


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


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.


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.


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


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)


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.


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


% 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.


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


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.


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


% 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

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Attachments

Granule friability


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



CP variability middle, smaller bottom, smaller middle, smaller middle, smaller


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


RNP: outliers none none none none


Deleted none none none none

Attachment 10. Overview data flowability

Attachment 11. Interaction effect plot for flowability

True density



CP variability middle, smaller bottom, smaller middle, smaller middle, smaller


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


RNP: outliers 14 none none none


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



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





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



CP variability middle, smaller middle, smaller top, smaller bottom, smaller


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



RNP: plot straight line straight line straight line straight line, ex CP


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



CP variability middle, smaller middle, smaller top, smaller bottom, smaller


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


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

GHENT UNIVERSITY FACULTY OF PHARMACEUTICAL SCIENCES

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