University of Groningen

Fundamentals of the high-shear pelletisation processRamaker, Johanna

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Publication date:2001

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In pharmaceutical application, an agglomeration process that results in agglomerates of a

rather wide size distribution within the range of 0.1 – 2.0 mm, with a high intra-agglomerate

porosity (about 20 – 50 %) is named a granulation process, and the agglomerates are called

granules.

If the final agglomerates are spherical, free flowing, and of a narrow size distribution in the

size range of 0.5 – 2.0 mm, and a low intra-agglomerate porosity (about 10 %), the process is

often referred to as pelletisation process, and the agglomerates are called pellets.

Particle size enlargement by pelletisation is often desirable for several reasons:1,2

1. Prevention of segregation of co-agglomerated components, resulting in an improvement

of the content uniformity.

2. Prevention of dust formation resulting in an improvement of the process safety, as fine

powders can cause dust explosions and the respiration of fines can cause health problems.

3. Increasing bulk density and decreasing bulk volume.

4. The defined shape and weight may improve the appearance of the product.

5. Improvement of the handling properties due to the free-flowing properties of pellets.

6. Controlled release application of pellets due to the ideal low surface area-to-volume ratio

that provides an ideal shape for the application of film coatings.

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Typical disadvantages of pellets and pellet production are:

1. Often pellets can not be pressed into tablets because they are too rigid. In that case, pellets

have to be encapsulated into capsules.

2. The production of pellets is often an expensive process and/or requires highly specialised

equipment.

3. The control of the production process is difficult e.g. the amount of water to be added is

very critical and overwetting occurs easily.

Pelletisation is used in various industries, like the pharmaceutical industry (controlled release

preparations), agricultural industry (fertilisers and herbicides), mineral processing (iron ore

pelletisation), food and detergents industry.

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Granulation in general can be divided into low-shear granulation, for example in a fluid bed,

where the movement of the particles is induced by an air steam, and medium/high-shear

granulation, where the particle movement is induced by means of forceful mechanical mixing

(for example using an impeller or a rotating plate). Medium-shear granulation occurs for

example in a rotating drum or planetary mixer. High-shear granulation is performed in a

rotary processor (marumerizer) and a high-shear mixer (figure 1.1).

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Figure 1.1. Schematic presentation of different pelletisation devices: a. rotating drum; b. high-shear

mixer Gral; c. rotary processor (marumerizer); d. extruder.

Pelletisation can be performed in medium-shear mixers as well as in high-shear mixers. The

following apparatuses are described in literature as pelletisation equipment (figure 1.1):

- pan and drum mixers, which have been described by many authors3-7;

- high-shear mixers, as described systematically by Schæfer and Kristensen8-10;

- rotary processors, as extensively described by Holm et al.11-13 and Vertommen14;

- extrusion (and spheronisation) equipment, as introduced by Reynolds15, and reviewed by

Vervaet et al.16

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This thesis focuses on the pelletisation process in high-shear mixers (typically a Collette Gral

or a coffee grinder). The results will often be compared with other high-shear granulation

processes, and with the rotating drum pelletisation process (which is a medium-shear

process).

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The pelletisation process in a high-shear mixer can be divided into several stages:

1. premixing of the solids;

2. liquid addition stage;

3. wet massing stage;

4. drying stage.

In the equipment used in this thesis, the first three stages take place inside the high-shear

mixer. The drying stage occurs in an oven (tray-drying).

The formation of pellets occurs during the liquid addition stage and the wet massing stage.

Growth (see 1.3.3) of pellets starts with the nucleation stage, occurring during the liquid

addition stage. The nucleation stage will be discussed in chapter 2. Further growth of pellets

occurs by fast growth (linear as well as exponential growth). Breakage of pellets also takes

place. Depending on the ratio of the amount of growth and breakage, an equilibrium stage can

be obtained in pellet growth.

The Collette Gral (figure 1.1b) high-shear mixer is equipped with:

- an impeller, rotating at the bottom of the bowl;

- a chopper, rotating near the wall of the bowl;

- a nozzle to supply the binder liquid.

The impeller rotational speed can easily be changed during processing. Therefore it is

possible have different rotational speeds, for example during the different stages of the

pelletisation process.

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Granulation processes in a high-shear equipment have often been considered as ‘black-boxes’

in which the starting material is converted to granules17. Changes of the process variables are

mainly based on trial and error. A real understanding of what’s going on is still missing.

Therefore, one has to take a careful look at the process and literally take the cover of the bowl

to look inside the ‘black-box’ (figure 1.2).

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Figure 1.2. Black-box approach.

By taking a careful look at the high-shear pelletisation process, three remarkable facts can be

seen. First, properties of the produced pellets depend strongly on the starting materials, the

apparatus, and the process conditions. This certainly can be a problem during upscaling,

because apparatus variables may change during upscaling resulting in changed pellet

properties.

Second, the pellet size distribution and pellet shape change during pelletisation, and depend

on the binder content (and the kind of binder used), processing time and impeller rotational

speed. More binder liquid or an increased processing time generally results in larger and more

spherical pellets, until the breakage of pellets becomes more important than the growth of

pellets, resulting in a decrease of the mean pellet size and the sphericity. A higher impeller

rotational speed causes faster growth and breakage of pellets. Depending on the ratio of

growth rate and breakage rate, this results in larger and more spherical pellets (more growth

than breakage), or smaller and less spherical pellets (more breakage than growth). Finally,

especially for the high-shear pelletisation process, a characteristic flow profile (e.g. torus) is

observed as soon as the pellets have been formed (see chapter 4).

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In order to know what happens on the scale of a particle, you can try to imagine yourself

being a particle inside a high-shear mixer. Try to understand what happens to you as a

particle. You will be swept through the bowl by the impeller. You will meet the wall and

collide with many other particles. At a specific moment, a splash of water will be dropped on

you, which wets you within a short period of time, leaving a small layer of liquid on you. As

soon as you meet some other particles again, they will stick on to you, and a granule has been

formed. A few moments later, you are being cut into several pieces by the impeller or the

chopper. That’s granulation!

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The method of ‘trial and error’ is still widely used for changing the process variables of the

granulation process to improve pellet properties. This method highly depends on the

experiences and creativity of the pharmaceutical scientist and the technician. Applying

experimental design is a more sophisticated approach18-21. With this procedure, the influence

of different processing variables as well as their mutual interactions can be investigated. And

the sensitivity of a number of processing variables can be investigated at the same time.

Although the effect of the processing variables can be described with this method, these

effects are often not (mechanistically) understood and extrapolation of the results is therefore

not allowed. Therefore, it is better to try to understand the influences of the processing

variables on the granule properties from a mechanistic point of view.

To understand the high-shear pelletisation process, one can try to develop mechanistic models

for this process. In literature, some fruitful modelling has been performed by several authors,

like Hounslow et al.22 who used the population balance modelling to model the particle size

distribution during the granulation process, Iveson et al.23 who gave an overview of the whole

granulation process by drawing a granulation regime map, and Wellm24 who modelled the

torque development during the granulation process.

These approaches make it possible to look inside the black-box and try to understand what

really goes on. Such a method also gives the possibility to predict the influence of a change of

the apparatus, the process, or the formulation (i.e. ingredients).

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Changes of the design and functionality of the impeller may increase the efficacy of the

energy input for the process and therefore diminish the unused dissipation of this energy.

Holm25 and Schæfer et al.26 changed the impeller design in order to create more densification

of the granules, which finally resulted in a narrower particle size distribution and more

spherical granulesCovering the wall of the bowl with PTFE-tape or coating was used by

several authors25,27,28. Due to this tape, less adhesion of granules on the wall was found,

resulting in a more homogeneous liquid distribution, resulting in a more controllable

granulation process.

Another way of changing the apparatus was recently published. A new sampling method was

described by Thies and Kleinebudde28, a cylinder of 2 cm was placed in the mixer wall.

Through this cylinder, several representative samples can be taken from one batch during

granulation without interrupting the process.

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Changes of the process conditions can be performed in order to reduce the amounts of fines

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and oversize granules which otherwise have to be either disposed of or recycled into the

process. So, process changes can be introduced in order to reduce the costs and the

environmental contamination. These changes include an optimisation of the impeller

rotational speed, chopper rotational speed, processing time, load of the bowl, the method or

rate of liquid addition, etc. There are many sound articles concerning the high-shear

pelletisation process24,29,30, the comparable melt pelletisation process5,8, and the production of

pellets in the rotary processor11,14.

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Microcrystalline cellulose (MCC) is world-wide the most used pelletisation aid. It would be

interesting to look for other excipients that also can be used as pelletisation aids. Because not

much literature about this subject is available, and the high-shear pelletisation process has

some aspects in common with the extrusion and spheronisation process, some literature about

this last field will be discussed. Kleinebudde et al.31 used a mixture of microcrystalline

cellulose (50-70 %, MCC), low-substituted hydroxypropylcellulose (0-20 %, L-HPC), and

acetaminophen (30%) for the preparation of pellets with the extrusion and spheronisation

method, and found a decreased water-sensitivity of the process and good dissolution

properties of acetaminophen from the pellets. But still, more than half of the formulation

existed of MCC. In comparison, the minimal amount of MCC needed to form a continuous

network, the so-called percolation threshold, is about 14 %32. At any volume concentration

higher than 14 %, MCC has formed a continuous network. So, in order to find other

excipients than MCC (for example a mixture of different materials) suitable for pelletisation,

the amount of MCC in this mixture has to be below 14 %. In 1994, Lindner and Kleinebudde

reported a study using powdered cellulose as pelletisation aid33. The pellets obtained with

powdered celluloses showed higher porosities and faster releasing properties compared to

those made with MCC. Since this study, a few more studies were reported concerning the

search towards more products that could be used as pelletisation aids. Chatlapalli et al.34

prepared pellets containing hydroxypropylmethylcellulose (HPMC) and hydroxyethyl-

cellulose (HEC) and used isopropyl alcohol as granulation liquid. Both HMPC and HPC were

found to be suitable pelletisation aids. Also a mixture of MCC (11 %) and β-cyclodextrine (89

%) was reported as a suitable extrusion / spheronisation agent giving satisfactory products35.

With this formulation, the amount of water needed to obtain good quality pellets was highly

decreased.

As a conclusion it can be stated that questions like “why is microcrystalline cellulose such a

good pelletisation agent”, and “is it possible to find other excipients except from

microcrystalline cellulose that can be used for the preparation of pellets” still are mostly

unanswered. Using melt pelletisation as an alternative for the high-shear pelletisation

technique, i.e. using a meltable binder, a series of pelletisation agents can be used, such as

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polyethylene glycol (PEG)5,8,36, Gelucire37, glycerol monostearate38 or stearic acid39. Because

MCC is so frequently applied it has also been used in the work described in this thesis.

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Granulation became a subject for scientific study in the second half of the 1950s; the forces

between the primary particles were among the first subjects investigated. Rumpf40 identified

in his fundamental work the categories of forces holding the granules together (figure 1.3):

- Attractive forces, like gravitational, magnetic, electrostatic and van der Waals forces. All

those forces are important during the handling of fine dry powders. In case of the

pelletisation process, those forces are more than one order of magnitude smaller than the

capillary forces, and thus not significant.

- Solid bridges, due to inorganic bonding, chemical reaction, crystallisation, melting at

points of contact due to frictional pressure, and sintering. Solid bridges can also be formed

after hardening of the binder liquid, which is of great importance during melt pelletisation.

- Particle interlocking. These bonds can be very important in the pelletisation process

because of the different shapes of the starting materials - crystals, rounded, or elongated -

and the high-shear forces acting on the pellets during processing.

- Liquid bridges, which can act in several ways to hold the granule together. The strength of

the liquid bridge is caused by the capillary pressure due to the curved surfaces, and the

interfacial tension. Liquid can also be adsorbed on the particle surface forming

multilayers. These multilayers can act as a lubricant to reduce the inter-particle friction.

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Figure 1.3. The most important inter-particle forces for pelletisation: a. solid bridges; b. particle

interlocking; c. liquid bridges.

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Newitt and Conway-Jones3 described in their pioneering research on the granulation process,

the different stages of liquid bonding in a granule as the pendular, funicular, capillary and the

droplet stage (see figure 1.4).

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Figure 1.4. Different stages of saturation for liquid bonds in granules: a. pendular stage; b. funicular

stage; c. capillary stage; d. droplet stage.

Before any liquid is present, and no liquid bridges can be formed, small aggregates of powder

can exist, held together by attractive forces like van der Waals forces. In the pendular stage,

only minor amounts of liquid are present, and the particles are held together by liquid bridges

present only at the contact points of individual primary particles. In the funicular stage, the

amount of liquid is increased, so that some of the liquid bridges can coalesce and form links

between more than two primary particles. The voids between the liquid bridges are partly

saturated with liquid. In the capillary stage, the voids are fully saturated with liquid, which

provides the strongest granule. At the surface, the liquid is drawn back into the pores under

capillary action, and inside the granules, the particles are completely surrounded with liquid.

If more liquid is added, the strength of the granule decreases rapidly, and the granule will be

converted into a system with particles suspended into the liquid or a paste. This is the so-

called droplet stage.

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A number of granule growth and breakage mechanisms, described by several authors 3,41-43

are illustrated in figure 1.5.

Figure 1.5. Mechanisms of granule growth and breakage, after Sastry et al.42

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Granule growth starts with nucleation, where primary particles stick together after being

wetted by a liquid drop. Also the engulfment of powder particles in a droplet is a part of the

nucleation mechanism.

Coalescence is the mechanism in which two granules collide with each other and form one

larger granule. After some surface deformation, a new spherical granule can be formed. The

maximal granule size above which no more coalescence takes place, and the chance of

sticking or non-sticking (=rebound) of a granule, have been topics of several investigations

(for example Ouchiyama and Tanaka44, and Ennis et al.45).

Layering, also called snowballing, is the mechanism in which many primary particles (e.g. the

non-granulated starting material) stick on the surface of a larger granule, due to the formation

of capillary bridges.

There is no distinct difference between the mechanisms coalescence and layering. In fact,

only the size of the initial particles differs. Coalescence assigns all successful collisions

between two granules, while layering is the mechanism in which primary particles stick on to

a larger granule.

Breakage of granules has been divided in literature into several mechanisms43. First of all

crushing, in which smaller granules are crushed and subsequently distributed over the surface

of the remaining granule by layering. Crushing can occur by shattering, fragmentation, or

abrasion. The other breakage mechanism referred to in literature is abrasion transfer. In this

mechanism material is transferred between two colliding granules, leaving both intact. This

mechanism has been identified experimentally41, but is thought to have a negligible effect on

the final granule size distribution.

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The strength of a liquid bridge formed by a collision between two particles determines

whether rebound or coalescence occurs. This force, which is among others a function of the

amount of liquid between the (spherical) particles relative to their volume, has been calculated

by Rumpf40. The maximum value of this force can be described as:

plcap dF αγ= (1.1)

where 1.9 < α < π depending on the moisture content (volume liquid to volume particle ratio),

γl relates to the surface tension of the binder liquid, and dp to the granule diameter.

For the breakage of granules, another equation based on fundamental research of Rumpf40 has

to be used. The tensile strength of granules (σt) in the funicular or capillary stage (see figure

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1.4) is defined as:

( )θ⋅γ

⋅ε

ε−⋅⋅=σ cos1

pp

lt d

SC (1.2)

in which C is the coordination number, depending on the particle shape, S is the liquid

saturation, ε is the intra granular porosity, dpp is the diameter of the primary particle, and θ is

the contact angle. The liquid saturation of a granule is defined as:

l

sHSρρ

⋅ε

ε−⋅= 1(1.3)

where H is the moisture content, which can be calculated as the ratio between the liquid mass

and the (dry) solid mass. The powder- and liquid densities are assigned by ρs and ρl,

respectively. The characteristic relationship between the liquid saturation and the tensile

strength of granules, as investigated by Schubert46, is schematically given in figure 1.6.

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Figure 1.6. Relationship between tensile strength of wet granules and the saturation, after Schubert46. Sp

denotes the end of the pendular state, and Sc the end of the capillary state.

Besides the properties of the starting material, the tensile strength of a granule highly depends

on the porosity and the liquid saturation. A high saturation and a low porosity provide strong

granules. Equation 1.2 is based on the static strength of the liquid bridges between the

particles. Under dynamic conditions, this equation does not exactly give the granule tensile

strength, which will be discussed in greater depth later.

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Ouchiyama and Tanaka44,47 derived a model for the estimation of the critical diameter above

which no coalescence occurs. This critical diameter (dc) can be calculated with:a

tc Kcd

σ⋅⋅= 23

(1.4)

Here, a and c are constants, K is a deformability constant, σt is the tensile strength of the

granule. The diameter dc is the specific diameter at which the chance on coalescence between

two granules theoretically is zero. The deformability constant K is defined as the ratio

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between the contact area (A) and the compaction force (F):

F

AK = (1.5)

This equation is only valid in case of total plastic behaviour of the granule.

Kristensen et al.48,49 measured the mechanical properties of moist granules, and used an

extended model of Ouchiyama and Tanaka to calculate the tensile strength of these moist

granules. The calculated tensile strength values are based on the principle that a limiting

strength of the moist granules must be gained before growth by coalescence becomes

possible. The granules gain strength by densification facilitated by the addition of binder

solution and agitation. Densification is a decrease in intra-granular porosity, which results in

an increase of the pellet saturation (eq. 1.3) leading to an increased pellet deformability, and

an increase of the tensile strength of the pellet (eq. 1.2) as long as S < Sc.

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Ennis et al.45,50 recognised the importance of the effect of viscosity on the strength of a liquid

bridge and developed an agglomeration model based on the dynamic liquid bridge.

Depending on the kinetic energy during the approach and the energy dissipated during the

collision, either rebound (non-successful collision) or coalescence (successful collision) of the

pellet occurs (figure 1.7). Ennis et al.45 defined the dimensionless viscous Stokes’ number for

such a system:

ηρ

=9

8 0rvSt p

v (1.6)

where ρp is the pellet (or granule) density, v0 is the relative velocity between the two spheres, r

is the pellet (or granule) radius, and η is the viscosity of the binder liquid.

K

KD

Y�

U

Figure 1.7. Ennis approach of the collision of two pellets.

This viscous Stokes’ number is a measure of the ratio of the collision energy to the viscous

dissipation brought about by the binder liquid. In a high-shear mixer, the impact velocity is

directly related to the tip velocity of the impeller (vtip = πND, with N is the impeller rotational

speed, and D the diameter of the bowl).

A collision between two pellets results either in rebound or coalescence. Since the collision

gives rise to loss of kinetic energy, the velocity before impact (v0) will be larger than the

velocity after impact (v). Coalescence occurs if Stv is lower than a critical value of the viscous

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Stokes’ number (Stv*). This critical viscous Stokes’ number is given by:

+=

av h

h

eSt ln

11* (1.7)

where e is the coefficient of restitution based on linear velocity differences of the pellets after

and before impact (as will be discussed in greater depth in chapter 4). The thickness of the

liquid layer on the surface of the pellet is given by h, and ha represents the characteristic

length of the surface asperities (the radius of the starting primary particles can be taken as a

measure herefore, see figure 1.7).

Three granulation regimes have been defined in terms of the magnitude of the Stokes’ number

(Stv) in comparison to the critical Stokes’ number (Stv*):

Stv « Stv* non-inertial regime, all collisions are successful;

Stv = Stv* inertial regime, some collisions are successful;

Stv » Stv* coating regime, no collisions are successful.

Granule growth by coalescence is promoted at low values of Stv and high values of Stv*. From

equations 1.6 and 1.7, it can be seen that the probability for a successful collision, and as a

consequence the granules growth rate, is increased by a lower particle density, a lower

impeller speed, a smaller granule size, a higher binder viscosity, a lower coefficient of

restitution, an increased surface liquid layer, and a smoother surface (or smaller primary

particles). Because some of these variables also depend on the time-effects and the moisture

content, it will be difficult to estimate the exact values of h, ha, and e experimentally.

Therefore, the use of this theory is limited to retrospective argumentation.

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Material properties of the materials involved are the most important variables during the

pelletisation process. For a material to be pelletised, the combination between the plastic and

the elastic properties of this material must have an optimal value. An improvement of the

model of Ouchiyama and Tanaka44 and Kristensen et al.49 has been made by Iveson et al.7,23

The latter compared the deformation behaviour, process intensity and liquid saturation with

the granule growth behaviour of granules made from varying materials. The rate of granule

consolidation was described by Iveson et al.23 with the deformation number, e.g. the ratio of

the impact pressure of the impeller (ρpvi2) and the yield pressure of the wet granules or pellets

(Yp). The relationship between the deformation number and the granule saturation resulted in

the design of a regime map for granule growth (figure 1.8). The granule growth regime map is

based on an extensive literature research for different materials and granulation processes and

some additional experiments.

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Pore Saturation =

Nucleation onlyInduction

Decreasig Induction Time

Increasing Growth Rate

Steady Growth

RapidGrowth

Slurry/Over-Wet

Mass

“Crumb”“Dry”Free-

FlowingPowderIncreasing

DeformationNumber,

100 %0 %

Crumb

Crushing&

Layering

Coalescence

Coalescence

H⋅ρρ⋅

εε−

l

s

min

min1

p

ip

Y

vDe

2ρ=

Figure 1.8. Granulation regime map, after Iveson et al.23

As can be seen in figure 1.8, a low deformation number leads either to nucleation or to

induction time growth. Higher liquid saturation generally causes faster granule growth due to

the increased surface plasticity and surface free-liquid present to form capillary bonds.

Furthermore, a high process intensity or a low wet granules deformation propensity increase

the granule growth rate. Considering the high-shear pelletisation process, a high mixing

intensity is obtained (high vi). In combination with the plastic deformation properties of the

wet pellets, a steady growth should be expected. More liquid saturation should finally lead to

rapid growth. If more liquid would be added, overwetting occurs and a slurry would be

formed.

This regime map is the first of its kind. It includes a number of parameters of interest, and has

a great potential to predict granulation behaviour from product and process characteristics. It

should make the control of granulation processes much easier.

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Randolph and Larson51 developed the first principles of the population balance describing the

number balance of the formation of crystals. As the granulation process can be described

similarly, the approach of Randolph and Larson has been adopted into this field. The basis

equation of the population balance is given by:

( ) DBGnt

n −=⋅∇+∂∂

(1.8)

where n is the number density of granules of a specific size at a specific time; G is the growth

rate of granules; B is the birth rate density of granules; and D is the death rate density of

granules.

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This equation can not be solved analytically, so solutions have to be obtained numerically by

discretisation. Hounslow et al.22 have developed the population balance equation further by

using different geometrically scaled size intervals, in which the size of the particles in the next

size class is twice the size (volume) of the particles in the current one.

The population balance of Hounslow et al.22 is given by:

∑ ∑∑−

=

∞

=

−−−−

−

=−−

+− β−β−β+β=1

1,,

211,1

2

11,1

1 22

12

i

j ijijjiijji

ijiii

i

jijji

iji NNNNNNNdt

dN(1.9)

where Nj represents the number of particles of size class j, dNi/dt is the change of the number

of particles of size class i as a function of time, and β is the coalescence kernel (note that this

kernel is a rate-constant, not a nucleus as described in chapter 2).

Assumptions of this population balance are:

- only binary collisions take place;

- conservation of volume during coalescence, which excludes any porosity changes during

the process;

- the conditions are uniform throughout the granulator, segregation of granules is not

included in the balance, and the impact forces are supposed to be constant in the whole

granulator;

- the coalescence kernel (β) is known;

- coalescence is the only granule growth mechanism, excluding nucleation;

- no granule breakage occurs. But during granulation in high-shear mixers breakage by the

impact of the impeller and the chopper does certainly occur.

There is no procedure for choosing the coalescence kernel form. Even if a good fit is found,

there is no guarantee that this is unique, that it is the best, or that it has any physical basis52.

There is a large number of proposed kernels in the literature42,43,45,53, but there is no a priori

justification which kernels are appropriate for a given granulation system, and a physical

interpretation of the coalescence kernel is still missing.

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Down-scaling experiments can be performed in such a way that these experiments are

representative for the large production scale. This is crucial. Other requirements for small-

scale apparatus and small-scaled processes are:

- rapid and reproducible experiments;

- cheap experiments;

- similar formulation;

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- geometric similarity with the large scale is not necessary, provided that dynamic similarity

of the particles exists (equal forces on the particles as a function of time). In fact this

means that the experiments are representative for the full scale.

Being more specific and remembering the part ‘imagine yourself being a particle’ (section

1.2.1.1), the following aspects are important:

- who you meet: smaller particles (for example primary particles), colleagues (of almost the

same size) and large particles (lumps), the impeller, the wall, or water droplets;

- under what conditions: water content and velocity differences;

- how often: number of meetings, in total or as a function of time (frequency).

If these aspects are identical at different scales, the development of the properties of the

particles (e.g. diameter, porosity) as a function of time, P(t), will be the same. This is the

fundamental basis of scale down, a concept that will show-up from time to time in this thesis.

Some remarks regarding these requirements can be made:

1. Not all aspects are always important.

2. A typical scale-down experiment is often limited to one or two aspects (e.g. the influence

of tip speed on mixing, or on growth and breakage of pellets). However, this is often also

true for classical (scale-up) experiments of complicated processes (due to the impossibility

to keep all relevant dimensionless numbers at a constant value during scale-up).

3. The advantage of scale-down is two fold. First it gives more experimental room for

manoeuvre (no geometric similarity needed). Second it provides rapid insight in the

relative importance of the different mechanisms that are potentially involved.

4. It is not always necessary to realise exactly the same value of the aspects at different scales

of operation. The same order of magnitude is often sufficient (e.g. to find the most

important mechanisms involved).

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There are several dimensionless numbers, which can be used for scale-up purposes:

- Power number: relationship between the power input and the power transferred to kinetic

energy (∆P/N3D5ρ).

- Reynolds number: describing the relationship between frictional forces and the

consistency of the wet mass (ρND2/η).

- Relative swept volume: fractional volume of the total batch size which is displaced by the

impeller in a specific time range (~N)

- Tip velocity: velocity of the impeller at the tip of the impeller arm (πND). The tip velocity

of the impeller arm can be used for scale-up in order to maintain a constant maximal shear

rate.

- Froude number: relationship between the centrifugal force and the gravity force (N2D/g).

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In literature, different methods of scale-up have been reported. The relative swept volume has

been considered to relate to the work input on the material which is assumed to provide

densification of the wet mass54,55.

Horsthuis et al.56 used the Froude number in order to scale-up in the Gral, whereas the relative

swept volume and a constant tip speed did not result in a comparable process.

A power consumption curve has been used by Leuenberger et al.57 for scale-up purposes. The

relationship between the power consumption and the amount of moisture added looks very

similar to the saturation curve derived by Schubert46 (figure 1.6). The process is stopped as

soon as the power consumption curve is at the desired value and the wet mass reaches the

desired consistency.

Cliff and Parker58 showed that the ratio between the power number and a pseudo Reynolds

number was independent of the scale of operations used (a pseudo Reynolds number was used

because the wet mass consistency ‘η’ was measured with a mixer torque rheometer in the

dimensions Nm instead of Pas). This method could therefore be a useful tool during scale-up.

Landin et al.59 and Faure et al.60 incorporated also the Froude number into this ratio in order

to find a scalable function.

Dry granules have another tensile strength than moist pellets, and tend to undergo brittle

fracture43. Therefore it is desirable to know the material properties of the wet pellets instead

of the dry pellet properties. The granule strength only gives important information about the

granulation process if it is measured as a wet-granule strength. The mixer torque rheometer

can give important information about the rheology of the granulate. The mixer torque

rheometer61-64 can easily be used as a down-scaled high-shear mixer. But, using this device,

one has to bear in mind the differences in apparatus-design, and impeller speed. The impact

velocity of the mixer torque rheometer and of the high-shear mixer should be of the same

order of magnitude in order to be able to use the rheometer as a down-scaled high-shear

mixer. Otherwise there is no dynamic similarity, which could result in the development and

measurement of non-relevant material properties in the mixer torque rheometer.

���� 0DWHULDO�SURSHUWLHV�RI�PLFURFU\VWDOOLQH�FHOOXORVH

Microcrystalline cellulose (MCC) is described as a purified, partially depolymerised cellulose

prepared by treating α-cellulose, obtained as a pulp from fibrous plant material with mineral

acids65. The cellulose fibres in the starting material are composed of millions of microfibres.

In the microfibres, two different regions can be distinguished: a paracrystalline region, which

is an amorphous and flexible mass of cellulose chains, and a crystalline region, which is

composed of tight bundles of cellulose chains in a rigid linear arrangement65. As an effect of

controlled hydrolysis, the amorphous fraction has largely been removed, yielding aggregates

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of the more crystalline portions of cellulose fibres. After purification by filtration and spray

drying, dry porous agglomerated microcrystals are obtained.

The requirements for the formation of pellets from a wet mass are as follows:66

1. The wet mass must possess sufficient mechanical strength if wet, yet it must be brittle

enough for lumps to be broken down to pellets, but not be so friable that the pellets

disintegrate completely.

2. The wet mass must be sufficiently plastic to enable the formation and spheronisation of

pellets in the high-shear mixer, thus decreasing the surface roughness.

The function of MCC herein is to control the distributions of water through the wet powder

mass during pelletisation, and to modify the rheological properties in the mixture, conferring

a degree of plasticity which allows for rapid pelletisation.

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The rheological properties of wet mass just before and after the formation of the pellets highly

depend on the liquid content of the wet mass. Only in a narrow range of liquid content it is

possible to produce round pellets of the desired size. Below this specific moisture content, the

plasticity of the wet mass is insufficient: in this case pelletisation parameters such as torque,

power consumption and temperature increase, and no pellets can be formed. Exceeding the

specific moisture content, results in lower values for the pelletisation parameters: the pellets

are soft and easily deformable. As a consequence, uncontrolled growth due to coalescence of

pellets occurs, or crumb is formed.

These observations can be described with strength of static liquid bonds in moist granules,

and lead to the model of different liquid states in moist granules3,40.

The liquid saturation model describes the relationship between the amount of powder and

liquid and the granule tensile strength, based on the different liquid saturation stages:

pendular, funicular, capillary, and droplet stage (see section 1.3.2). The same model is used to

describe the process during pelletisation. When water is added to a powder, the liquid will

occupy the spaces between the powder particles. The saturation of the powder mass can be

defined as the fraction of the pores between the powder particles, which is occupied by water

(eq. 1.3). The strength of the pellets depends on the saturation, porosity and size of the

starting material:

( )θ⋅γ

⋅ε

ε−⋅⋅=σ cos1

pp

lt d

SC (1.2)

Some restrictions of the liquid saturation model are:67

1. the equation of the tensile strength (eq. 1.2) of granules was developed for a liquid

saturation between about 25 % and 90 %;

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2. the tensile strength of wet pellets in the liquid saturation model is based on static liquid

bridges only;

3. particles are assumed to be spherical;

4. (partly) dissolving of the solid by the liquid is not included in this model;

5. porosity is assumed to be constant during process, and swelling of the solid in the liquid is

not included in the liquid saturation model.

During the extrusion and the pelletisation process with MCC, it has been observed that the

calculated saturation of pellets can be about 100 %68, the strength of the liquid bridge depends

also on the viscosity of the binder liquid50, the size and shape of primary MCC-particles are

not spherical and rigid69, and pellets containing MCC shrink during drying70. For these

reasons, the saturation model is not valid to explain the behaviour of MCC during extrusion

and/or pelletisation.

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Due to the passive water binding properties of microcrystalline cellulose (MCC), an amount

of about 16 – 26 % of water can be bound to MCC71. If more water is present (for example in

a MCC-water mixture during granulation), it has to be bounded in another way. Therefore,

MCC was addressed as a ‘molecular sponge’72 (figure 1.9a).

FU\VWDOOLWHV

ZHW VWDWH

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ZDWHU

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Figure 1.9. Schematic illustration of water in the cellulose samples. a. sponge model73; b. crystallite-gel

model.

Each particle of MCC would behave as a porous sponge and each particle would be able to

absorb a large quantity of water. Part of the water in MCC is absorbed in the pores inside the

cellulose fibres and amorphous regions, and part is located between the fibres with

obstruction and hydration interactions with the fibres73. All pores are supposed to be

completely filled with water. Under pressure the water would be partly squeezed out and

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lubricate a particle rearrangement. Water can also be taken-up again after releasing the

pressure while the volume increases. MCC particles remain intact during the process of

pelletisation, extrusion and spheronisation and should be of the same size, shape and volume

in the finished product compared to the original MCC powder74.

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Kleinebudde proposed the crystallite-gel model in which a gel is formed during extrusion /

spheronisation with MCC67. The concept of the crystallite-gel model could also be valid for

the pelletisation process.

It has been shown75 that powder particles of MCC are broken down into smaller sub-units due

to the presence of water and shear (for example during granulation and extrusion). Single

crystallites with a size of a few micron can be obtained. These single particles are able to form

a crystallite-gel and immobilise the water (see figure 1.9b). The crystallites or their

agglomerates can form a network by cross-linking with hydrogen bonds at the amorphous

ends. The viscosity of the gel depends on the water content and the degree of cross-linking

(e.g. the size of the resulting structural components). At increasing liquid content, the fraction

of gelling agent in the gel decreases and the deformability increases. The gel is not sticky,

because the gelling agent is not soluble in water.

The formation of hydrogen bonds in the amorphous ends of the crystallites during drying can

be described as an autohesion effect resulting in a stable matrix. (Autohesion is defined as the

mutual inter-diffusion of free polymer chain ends across the particle-particle interface of high

molecular weight polymers resulting in a stable link76.) This provides an explanation for the

disintegrating77 and dissolution properties19,78 of pellets.

The particle size of the MCC powder does not have any influence on the amount of binder

liquid needed for pelletisation (while it is reported that the amount of binder liquid needed for

pelletisation is influenced by the source of MCC67), which can be explained using the

crystallite-gel concept. After all, after formation of the crystallite gel, the size of the starting

material is not important anymore, whereas the amount of contaminations of the starting

material is.

The surface structure of MCC pellets is completely different from the structure of MCC

powder. The structure of the original powder particles disappeared completely and turned into

a coherent network. This suggests the formation of a network during pelletisation. And,

shrinking of the pellets during drying is supposed not to occur in the sponge-like approach,

which is another argument using the crystallite-gel model.

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The aim of this thesis is to obtain insight in the most important mechanisms involved during

the high-shear pelletisation process. The mechanisms of pellet growth and breakage are

investigated, as well as the flow profile of pellets inside the mixer, using a coffee-grinder as a

down-scaled high-shear mixer. By knowing the locations of pellets inside the mixer, and the

influence of the impeller, chopper, wall and other pellets on the pellet deformability and

strength, it should be possible to predict the pellet growth behaviour for a specific

combination of powder mixture, apparatus and process parameters.

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���� 1RPHQFODWXUH

a constant

A contact area (m2)

B birth rate density function (s-1)

C coordination number

c constant

d diameter (m)

D diameter of the bowl (m)

D death rate density function (s-1)

e coefficient of restitution based on linear velocity differences

F force (N)

g gravitational acceleration constant (m·s-2)

G growth rate (s-1)

h thickness of liquid layer on granule surface (m)

ha characteristic length of the surface asperities (m)

H moisture content

K deformability constant (Pa-1)

N impeller rotational speed (s-1)

N number of particles

n number density of granules

P power input (W)

r granule radius (m)

S liquid saturation

Stv viscous Stokes number

Stv* critical viscous Stokes’ number

t time (s)

v relative velocity (m.s-1)

Y yield pressure (Pa)

Greek symbols

α constant

β coalescence kernel

ε (intra-granular) porosity

γ surface tension (N.m-1)

ρ density (kg.m-3)

η viscosity (Pa.s)

θ contact angle (°)σt tensile strength (Pa)

Subscripts

c critical

i,j size classes

l liquid

p granule or pellet

pp primary particle (starting material)

s solid

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23. Iveson, S.M., Litster, J.D., Growth regime map for liquid-bound granules, AIChE Journal 44, 7 (1998)

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processor, Pharm.Dev.Technol. 1, 4 (1996) p. 365-371.

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pellets using extrusion-spheronization, Int.J.Pharm. 96 (1993) p. 119-128.

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microcrystalline cellulose tablets at low relative densities, Int.J.Pharm. 182 (1999) p. 243-255.

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extrusion/spheronization, J.Pharm.Pharmacol. 46, 1 (1994) p. 2-7.

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cyclodextrin as a pelletization agent in the extrusion/spheronization process, Drug Dev.Ind.Pharm. 24, 9

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36. Heng, P.W., Wan, L.S., Wong, T.W., Effect of off-bottom clearance on properties of pellets produced

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39. Eliasen, H., Kristensen, H.G., Schæfer, T., Growth mechanisms in melt pelletisation with a low

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45. Ennis, B.J., Tardos, G., Pfeffer, R., A microlevel-based characterization of granulation phenomena,

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46. Schubert, H., Tensile strength of agglomerates, Powder Technol. 11 (1975) p. 107-119.

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66. Fielden, K.E., Newton, J.M., , In: Encylcopedia of Pharmaceutical Technology., Vol. 5, eds. J.

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and spheronization, Pharm.Res. 14, 6 (1997) p. 804-809.

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low substituted hydroxypropylcellulose: I. Shrinking properties, Int.J.Pharm. 109 (1994) p. 209-219.

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