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The research project described in this thesis was performed within the framework of the

research school GUIDE.

Printing of this thesis was financially supported by:

AVEBE, Foxhol, The Netherlands

RijksuniversiteitGroningen, The Netherlands

J.S. Ramaker, Groningen, The Netherlands, 2001

Printing: Stichting Drukkerij C. Regenboog, Groningen, The Netherlands

ISBN: 90-367-1392-7

Electronic version ISBN: 90-367-1400-1


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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 improvementof 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).

D E

F GFigure 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 Schfer 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 byVervaet 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-shearmixer. 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 whats 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 beseen. 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 ofpellets, 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. Thats 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. Applyingexperimental 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 Schfer 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.

3URFHVVFRQGLWLRQVChanges 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-shearpelletisation 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 hassome 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 werefound to be suitable pelletisation aids. Also a mixture of MCC (11 %) and-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 pelletisationtechnique, 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 theinterfacial 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.

D E FFigure 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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FE GDFigure 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 onelarger 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 thismechanism 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 determineswhether 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 = (1.1)

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

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


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,

1.4) is defined as:

( )

= cos1

pp

l

td

SC (1.2)

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

saturation, is the intra granular porosity, dpp is the diameter of the primary particle, and isthe contact angle. The liquid saturation of a granule is defined as:

l

sHS

=1

(1.3)

whereHis 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 s and l,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

= 2

3(1.4)

Here, a and c are constants, K is a deformability constant, t is the tensile strength of thegranule. 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 anextended 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:

=9

8 0rvSt pv (1.6)

where p is the pellet (or granule) density, v0 is the relative velocity between the two spheres,ris the pellet (or granule) radius, and is the viscosity of the binder liquid.

K

K

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 = ND, withNis the impeller rotationalspeed, andD 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 thevelocity after impact (v). Coalescence occurs ifStv is lower than a critical value of the viscous


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,

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

+=

a

vh

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 ofStv and high values ofStv*. 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 ofh, 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 withthe 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 (pvi2) 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

CrumbDryFree-

Flowing

PowderIncreasingDeformationNumber,

100 %0 %

Crumb

Crushing

&Layering

Coalescence

Coalescence

H

l

s

min

min1

p

ip

Y

vDe

2=

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 thewet 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; andD is the death rate density ofgranules.


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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:

=

=

=

+ +=1

1,,

211,1

2

11,1

1 221

2i

j ij

ijjiijji

ij

iii

i

j

ijji

iji NNNNNNNdt

dN(1.9)

whereNj represents the number of particles of size classj, dNi/dtis the change of the number

of particles of size class i as a function of time, and is the coalescence kernel (note that thiskernel 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 () 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.

6FDOLQJ

'RZQVFDOLQJ

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;


20/144

- 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 therelative 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).

8SVFDOLQJ

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 kineticenergy (P/N3D5).

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

consistency of the wet mass (ND2/).- 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 (ND). The tip velocityof 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).


21/144

,

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 usedbecause the wet mass consistency was measured with a mixer torque rheometer in thedimensions 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 thegranulation 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.

0DWHULDOSURSHUWLHVRIPLFURFU\VWDOOLQHFHOOXORVH

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

prepared by treating -cellulose, obtained as a pulp from fibrous plant material with mineralacids65. 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 ofcontrolled hydrolysis, the amorphous fraction has largely been removed, yielding aggregates


22/144

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 brittleenough 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.

/LTXLGVDWXUDWLRQPRGHO

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 willoccupy 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:

( )

= cos1

pp

l

td

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 liquidsaturation between about 25 % and 90 %;


23/144

,

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 isnot 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.

7KHVSRQJHPRGHO

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 sponge72 (figure 1.9a).

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


24/144

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.

&U\VWDOOLWHJHOPRGHO

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). Singlecrystallites 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 thecrystallite-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.


25/144

,

$LPRIWKLVWKHVLV

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 adown-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.


26/144

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 densityfunction (s-1)

e coefficient of restitution based on linear velocity differences

F force (N)

g gravitational accelerationconstant (ms-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 numberStv

* critical viscous Stokes number

t time (s)

v relative velocity (m.s-1)

Y yield pressure (Pa)

Greek symbols

constant coalescence kernel (intra-granular) porosity surface tension (N.m-1)

density (kg.

m-3

) viscosity (Pa.s) contact angle ()t tensile strength (Pa)Subscripts

c critical

i,j size classes

l liquid

p granule or pellet

pp primary particle (starting material)

s solid


27/144

,

5HIHUHQFHV

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gel model for extrusion and spheronization, Pharm.Res. 15, 4 (1998) p. 509-512.

75. Brittain, H.G., Lewen, G., Newman, A.W., Fiorelli, K., Bogdanowich, S., Changes in material

properties accompanying the national formulary (NF) identity test for microcrystalline cellulose,

Pharm.Res. 10, 1 (1993) p. 61-67.

76. Millili, G.P., Wigent, R.J., Schwartz, J.B., Autohesion in pharmaceutical solids, Drug Dev.Ind.Pharm.

16, 16 (1990) p. 2383-2407.

77. Pinto, J.F., Newton, J.M., Preparation and rapid disintegration tablets from pellets produced by

extrusion and spheronisation, World congress on particle technology 3, Brighton, UK (1998) p. 95.

78. Lundqvist, .E.K., Podczeck, F., Newton, J.M., Compaction of, and drug release from, coated drug

pellets mixed with other pellets, Eur.J.Pharm.Biopharm. 46 (1998) p. 369-379.


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&KDSWHU

1XFOHDWLRQVWDJHRIWKHKLJKVKHDUSHOOHWLVDWLRQSURFHVV

$EVWUDFW

A detailed description is given of the nucleation stage of the high-shear pelletisation process.

Colour experiments were performed in order to describe the distribution of coloured binder

liquid over the powder bed during the liquid addition stage. Based on these experiments the

destructive nucleation growth mechanism is defined. Pelletisation starts with the formation of

large primary nuclei. Small secondary nuclei are formed due to break-up of the primary

nuclei. The formation of the primary nucleus coincided with an increase in the energy input.

This nucleation process is described by the comparison of the theoretical tensile strength ofthe nuclei and the dynamic impact pressure. Due to densification, the secondary nuclei

become stronger and growth proceeds exponentially by coalescence. The experiments suggest

that the exponential growth depends linearly on the specific liquid addition rate and the

impeller speed. During the kneading stage, net growth diminishes until a steady state is

observed. The mean pellet size does not change during the final stages of the kneading phase

resulting in a well-defined product.

This chapter is based on:Vonk, P. Guillaume, C.P.F. Ramaker, J.S., Vromans, H., Kossen, N.W.F., Int.J.Pharm., 1997(157): p. 93-102.


33/144

1

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During the last few decades, much research has been done on granule growth mechanisms. A

pioneer in the investigations in granule growth mechanisms was the study of Newitt and

Conway-Jones1

. These authors precisely described the granule growth mechanisms ofmoistened sand in a rotating drum. They divided the granule growth into several steps,

starting with nucleation, followed by crushing and layering, and coalescence. The different

stages of granule growth were followed with colour experiments. This research led to the

fundamental basis of the description of the mechanisms of granule growth.

Since Newitt and Conway-Jones, many researchers have described the granule growth in

different apparatus and with different materials. Granulation in different apparatus results in

different granules. For example: the shear forces, geometric dimensions, liquid addition

method and processing time can be varied between the apparatus, resulting in more or less

densified granules with different size distributions. Consequently, for the understanding of the

granule growth mechanisms in each type of apparatus, one has to perform experiments based

on work done before.

The aim of this study is to investigate nucleation and growth of pellets during the liquid

addition and kneading phase of the pelletisation process in two different scales of Collette

Gral.

7KHRUHWLFDOFRQVLGHUDWLRQVThe pelletisation process consists of four stages:

1. dry mixing stage, in which premixing of the solids occurs

2. liquid addition stage,

3. wet massing stage, in which kneading of the wetted mass occurs,

4. drying stage.

Growth of granules and pellets, which occurs during the liquid addition stage and the

kneading stage, has been studied to a large extent2-4. Usually drum and pan granulations have

been investigated. These theories of the mechanisms of growth can not be translated directlyto high-shear pelletisation, because among other things, the physical circumstances are quite

different due to the high-shear forces present.

To understand the mechanisms of growth involved during the pelletisation process, it is

necessary to know the influence of the process variables. Many authors described the

influence of the liquid content and the process time on granule growth5-8. These studies are

often restricted to the removal of fines, the pellet growth during the kneading phase and

optimisation of the process by factorial design. So far, a precise understanding of the

underlying mechanisms and subsequent control over the process are still a topic of great

interest9.


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Coloured binder liquid can be used for the qualitative description of the distribution of the

binder liquid over the bowl content and for the identification of different growth mechanisms

during pelletisation. Different growth mechanisms can be clarified using coloured binder

liquid, because varying colour patterns on a cross-sectional area of the pellets indicate

different growth mechanisms of the pellets.Schfer and Mathiesen4 described two nucleation mechanisms for melt pelletisation, i.e.

immersion and distribution, depending on the ratio between the initial particle size and the

binder droplet size. Sastry and Fuerstenau10 described the nucleation of particles due to

collisions between particles with a wetted surface. Here, firstly the wetting of the particles

occurs (in most studies, wetting already has occurred because of the moistened feed materials

used in these experiments) and secondly the collision between the wetted particles. After the

nuclei are formed, further growth by coalescence and layering (or snowballing) takes place.

0DWHULDOVDQGPHWKRGV

Microcrystalline cellulose (Avicel PH101, FMC, Wallingstown, Ireland) and lactose

(Pharmatose 200 mesh, DMV, Veghel, The Netherlands) were used as starting materials.

Demineralised water was used as binder liquid (surface tension 0.072 N.m-1). Two

commercially available Gral vertical high-shear mixers (Collette, Wommelgem, Belgium),

Gral 10 (8 litre, impeller diameter 24 cm) and Gral 25 (25 litre, impeller diameter 36 cm),

were used for the preparation of pellets. The Gral 10 was equipped with strain gauges

attached to a computer, to measure the torque on the impeller shaft. The Gral 25 was equipped

with a power consumption meter, measuring the power consumption of the impeller motor.

To study the different mechanisms of pelletisation in high-shear mixers, the following

experiments were performed.

The first set of experiments examined the growth of the pellets during the pelletisation of

equal amounts of MCC and lactose with water. Table 2.1 gives the formulation and some of

the relevant material properties used.

Table 2.1. Formulation and material properties used during pelletisation.

material amount (kg)

Gral 10

amount (kg)

Gral 25

s (kg/m3) dgw (m)

MCC 0.4 1.25 1608 63

lactose 0.4 1.25 1540 45

water 0.43 1.25 1000

The liquid addition rate was set to 82 g/min by means of a peristaltic pump (type 5040,

Watson Marlow ltd.) and supplied by a nozzle (BLM 9 60, Delevan 1/8). The mean droplet


35/144

1

size was about 5 mm.

The impeller of the Gral 10 (Gral 25) was set at 430 rpm (276 rpm) during the liquid addition

stage, and chopper was set at 3000 rpm for both granulators. In this way, the tip velocities of

the impellers were kept constant at 5.2 m/s and a dynamic similarity between the two mixers

was obtained. The wet mass was subsequently kneaded for 15 minutes. During the kneadingstage the chopper was switched off. An additional experiment was performed in the Gral 10 at

an impeller speed of 650 rpm during the kneading stage. All pellets were tray-dried for 24

hours at 60C.

The pellet size distribution was measured at different stages during the liquid addition and

kneading stage. Each size distribution measurement was done with a new batch. The size

distribution of the starting materials (dpp) and the pellets (dp) were measured by means of laser

diffraction analysis using a Malvern 2600 laser diffraction apparatus using an 18 mm beam

expander, a 1000 mm lens, and a dry powder feeder. Also the porosity of some pelletsprepared in the Gral 10 was determined using an Autopore II (9220 v3.00) mercury

porosimeter.

The influence of the impeller speed (varying between 60 and 600 rpm) on the dimensions of

the nuclei in the Gral 10 was investigated, by preparing separate nuclei using indigotine t132

as colouring agent dissolved in the binder liquid (concentration 0.33 g/l). The coloured binder

liquid was added in one minute with a nozzle (82 gram binder liquid) after which the process

was stopped. The distribution of the coloured binder among the bowl content directly after the

liquid addition was qualitatively investigated. The wet nuclei were sampled, and thedimensions and weights of the dry and wet nuclei were measured. Also, the dimensions of the

core and the shell were measured on the cross-sectional area of the wet nuclei. From these

data, the strength of the wet nuclei could be calculated using equation 2.2.

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*URZWKRISHOOHWV

Growth of pellets was investigated by means of the pellet size, in which 10 % (d10), 50 %(d50) and 90 % (d90) of the volumetric pellet size distribution is smaller than the given value.

The d10, d50, d90-values of the Gral 10 and Gral 25 at different processing times are given in

figure 2.1 and figure 2.2 respectively. Figure 2.3 gives the growth of pellets at different

amounts of binder liquid.

The characteristics of the pellet growth in both mixers are rather similar. Initially minor

growth occurs, which is demonstrated by the horizontal lines of the growth curves. After 3

minutes of liquid addition for the Gral 10 (7.5 minutes for the Gral 25), the amount of largest

particles increases, which can be seen at the d90-value. This corresponds to the addition of 0.2g/g binder liquid, as can be seen in figure 2.3.


36/144

0

500

1000

1500

2000

0 5 10 15 20 25time (min)

diameter(

m)

Figure 2.1. Growth of pellets in the Gral 10 at an impeller speed of 430 rpm. Key: ( ) d10; ( ) d50; ( ) d90;

and( ) d50 of the Gral 10 at an impeller speed of 650 rpm during the kneading stage. End of liquid addition at

5:25 minutes is given with the dotted line.

Growth of the small- and medium-ranged particles starts after 4 and 10 minutes of liquid

addition for the Gral 10 and Gral 25, respectively (after the addition of approximately 0.3 g/g

binder liquid). Liquid addition is stopped after the addition of 0.5 gram liquid per gram solid.

If more liquid would be applied, overwetting of the solid mass will occur. The amount of

applied liquid thus has to be controlled within a specified range.

0

500

1000

1500

2000

0 5 10 15 20 25 30time (min)

diameter(m)

Figure 2.2. Growth of pellets in the Gral 25. Key: ( ) d10; ( ) d50; ( ) d90. End of liquid addition at 15:15

minutes is given with the dotted line.

Exponential growth of pellets is observed at the end of the liquid addition stage and the

beginning of the kneading stage. Growth of pellets in the Gral 10 at a binder liquid content of

0.45 g/g seems to be somewhat delayed. This is probably caused by adhesion of wet materialto the impeller and the wall of the Gral 10. Therefore, relatively less binder liquid is available


37/144

1

to cause pellet growth.

After the liquid addition stage, a 15 minutes period of kneading was applied. Here a distinct

difference between the two mixers can be seen. The pellets in the Gral 10 still grow

considerably, while the growth of pellets in the Gral 25 diminishes. This is mainly caused by

the different amount of total liquid applied to the powder mass. In the Gral 10, an extraamount of 7.5 % binder liquid was added to the powder mass. Due to this additional 7.5 %

binder liquid, the mean pellet size increases with approximately 35 %. This again shows the

large influence of the liquid content.

10

100

1000

10000

0 0.1 0.2 0.3 0.4 0.5 0.6

H (g/g)

diameter

(m)

Figure 2.3. Growth of pellets as a function of the liquid contents. Key: ( , ) d10; ( , ) d50; ( , ) d90. The

closed symbols are Gral 10-data, open symbols are Gral 25-data.

Higher impeller rotational speed in the Gral 10 during the kneading stage results in a smaller

d50-value (see figure 2.1). The net growth of the pellets seems to have stopped during the final

stages of the kneading phase. Usually granulation is ended while the mean granule size still

increases3,11,12. This requires accurate control of the process because of the risk of overwetting

and overgrowing of the pellets. Due to the non-changing pellet size distribution after 15

minutes of kneading, the endpoint determination is less critical in our process.

6PDOOVFDOHH[SHULPHQWV

'LPHQVLRQVRIWKHQXFOHL

The small-scale experiments in the Gral 10 were performed to characterise the nuclei during

the first minutes of the liquid addition stage. Immediately after one droplet reaches the

powder bed, it will adsorb powder and form a nucleus (immersion mechanism4). Because of

the wet surface of the nucleus, particles adhere to the nucleus and cause growth by layering.

As long as the outer surface of the nucleus still is wetted, growth by layering proceeds,resulting in the formation of the shell due to capillary suction13.


38/144

0

1

2

3

4

5

6

0 100 200 300 400 500 600

impeller rotational speed (rpm)

length(mm)

Figure 2.4. Relationship between the dimensions of the primary nucleus and the impeller rotational speed; ( )

total radius nucleus; ( ) radius core nucleus; ( ) length shell. Data points are mean of five measurements,including the standard deviation.

The dimensions of the nuclei, prepared in the Gral 10, are given in figure 2.4 and table 2.2.

All nuclei were coloured in the core, while the outer shell was less coloured or nearly

uncoloured.

The size of the core and shell varied depending on the impeller rotational speed (see figure

2.4). Smaller nuclei were found at higher impeller rotational speeds. This can be seen in the

decreasing size of the core and the outer shell of the nuclei. The size of the outer shellrelatively decreases more compared to the size of the core of the nucleus. Also, the core of the

nucleus consists of more liquid compared to the shell of the nucleus, which could be seen

clearly by the large amount of colour in the core of the nucleus. The strength of the

agglomerates relates linearly with the moisture content, and thus the amount of colour (see

equation 2.2 and 2.3). These findings indicate that the strength of the shell is less than the

strength of the nucleus.

6WUHQJWKRIWKHQXFOHL

The porosity of the nucleus () can be estimated with the following equation:

s

sVm

= 1 (2.1)

where ms is the mass of solids in the nucleus, V is the volume of the nucleus, and s is thedensity of the solids. With an initial droplet size of 4.7 mm the porosity of the nucleus at 600

rpm was equal to 0.63 (see table 2.2). This porosity corresponds with the bulk porosity of the

powder mixture (which is about 0.6). The tensile strength of the nuclei can be calculated with

the formula of Rumpf for the static tensile strength14

:


39/144

1

( )

pp

l

td

S

=cos1

8 (2.2)

Here t is the tensile strength of the nucleus, l the surface tension of the binder liquid, theangle of contact between the liquid and the solid ( ~ 0), and dpp the mean primary particle

size of the starting material. The saturation (S) is given by:

l

sHS

=1

(2.3)

HereHis the moisture content, calculated as the ratio of the mass of the liquid and the mass

of the solids, and l is the density of the liquid.The static tensile strength of the primary nuclei is in the order of several kPa (see table 2.2).

Table 2.2. Physical properties of the nuclei prepared in the Gral 10 at varying impeller rotational speeds.

60 rpm 150 rpm 250 rpm 400 rpm 600 rpm

m (g) 0.20 0.19 0.17 0.14 0.08

Vtot (ml) 0.45 0.42 0.37 0.26 0.14

Vl (ml) 0.09 0.05 0.08 0.06 0.05

(-) 0.72 0.72 0.71 0.67 0.63S (-) 0.20 0.15 0.22 0.24 0.39

t (kPa) 0.72 0.52 0.82 1.09 2.16

The solubility of lactose and the swelling properties of MCC make the use of the tensile

strength formula of Rumpf somewhat questionable. Lactose dissolves in the binder liquid,

lowers the surface tension, increases the viscosity and influences the porosity. The cellulose

absorbs large amounts of water, lowers the amount of lactose which can dissolve. A strong

indication of this can be found when scanning electron microscopic pictures are investigated

of the pellets before and after the dissolution of the lactose from the pellets. The lactose

crystals are clearly visible while the original structure of the cellulose particles can no longer

be recognised. Nevertheless, the order of magnitude of the tensile strength is used to compare

the tensile strength of the nuclei with the impact of the impeller.

'HVFULSWLRQRIWKHERZOFRQWHQW

Besides the dimensions of the nuclei, also the distribution of the fragments of these nuclei in

the bowl content was observed. The results of the distribution of the colour inside the Gral 10

are given in table 2.3. At a low impeller speed large primary nuclei are formed with a dark

blue core and a white shell, which do not break in the mixer. At impeller speeds of 150 rpm

and higher, the large (primary) nuclei are broken into smaller (secondary) nuclei of about 2

mm. These secondary nuclei can be identified by the light-blue colour. The size of the


40/144

secondary nuclei decreases at increasing impeller speeds. At an impeller speed of 400 rpm

breakage of the primary nuclei is nearly complete because only some large (primary) nuclei

and many small (secondary) nuclei are found. Breakage of the primary nuclei is complete at

an impeller speed of 600 rpm, when only small secondary nuclei can be recognised, and the

total bowl content is coloured blue. The nucleation process, as described above at 400 and600 rpm, results in the formation of dense secondary nuclei, and enhances the distribution of

the binder liquid.

Table 2.3. Results of the nucleus formation in the Gral 10.

impeller

(rpm)

impact (kPa)(eq. 2.8)

description of the bowl content

60 0.24 large nuclei are formed with blue nucleus and white shell

150 1.48 large nuclei together with some smaller nuclei due to break-up250 4.11 large nuclei together with some smaller nuclei due to break-up

400 10.5 some smaller nuclei and light blue colouring of powder mass

600 23.7 some smaller nuclei and more intense blue colouring of powder mass

,PSDFWRIWKHLPSHOOHUDUP

The result of the small-scale experiments can be used for the interpretation of the nucleation

stage of the pelletisation process in the Gral 10.At an impeller speed of 85 rpm the powder bed changes from a moving bed to a well-mixed

bed because the gravity force (Fg) becomes equal to the centrifugal force (Fcen):mgFg = (2.4)

( )( )D

NDmFcen

21

2= (2.5)

rpm58s1.42

1- ==

=D

gNc (2.6)

Here m the mass, g the acceleration due to gravity, N the impeller rotational speed,D the

diameter of the bowl, andNc the critical impeller speed. The powder bed will be moving in a

chaotic, fluidised manner, and droplets will fall on to a cloud of powder particles.

To explain the breakage of nuclei, the estimated tensile strength of a primary nucleus is

compared with an order of magnitude estimation of the impact pressure caused by the impact

on a nucleus by the impeller. In order to calculate the impact pressure, the acceleration of the

nucleus on impact has to be estimated. The acceleration (a) is estimated by:

p

tip

tip

d

vv

t

va

= (2.7)


41/144

1

Better estimations of the acceleration can be found using rigorous mathematical models like

the distinct element method15,16. When the estimated acceleration is used, the impact pressure

of the impeller is given by:

22

241

361

24 3

2tipp

p

tip

pp

p

pimpact vd

v

d

d

d

ma

A

F

===

(2.8)

Here impact is the impact pressure, Fthe acceleration force,A the cross-sectional area of thepellet, m the mass of the nucleus, a the acceleration of the nucleus, dp the diameter of the

nucleus, p the density of the nucleus, and vtip the tip velocity of the impeller (=ND). Theimpact pressure of the impeller arm is also given in table 2.3.

In figure 2.5, the strength of the nuclei (table 2.2) is compared to impact pressure of the

impeller arm (table 2.3). Figure 2.5 shows that at impeller speeds between 60 rpm and 150

rpm, the impact pressure of the impeller arm is of the same order of magnitude as the tensile

strength of the nuclei. In this range of impeller speeds, breakage of the primary nuclei can justbe expected, which is confirmed by our observations. At higher impeller speeds, breakage of

smaller nuclei takes place and distribution of the crushed fragments of these nuclei in the

bowl proceeds rapidly due to the intense mixing in the Gral.

0

5

10

15

20

25

0 100 200 300 400 500 600

impeller rotational speed (rpm)

tensilestrengthor

impactpres

sure(kPa)

Figure 2.5. Tensile strength of the nuclei ( ) compared to the impact pressure of the impeller arm ( ) at

varying impeller rotational speeds.

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In order to characterise the pellets, mercury porosimetry was performed on dry pellets from

three batches prepared in the Gral 10. The impeller speed during the kneading phase was set

to 650 rpm to enhance the effect of the kneading phase. The prepared batches were taken at t

= 5:15 minutes (just before the end of the liquid addition), at t = 7:25 minutes (2 minutes

kneading) and at t= 20:25 minutes (15 minutes kneading). Table 2.4 gives the porosity data

of the dry pellets of different sieve fractions.


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Table 2.4. The porosity of the Gral 10 pellets.

Time (min) size class (m) porosity size class (m) porosity

5:15 200-500 0.117 1250-1500 0.194

7:25 200-500 0.062 1250-1500 0.08120:25 850-1200 0.023 1250-1500 0.018 porosity is calculated with the total pore volume between 0.2 m and 10 m. amount pellets in sieve fraction 200-500 m was not large enough to measure the porosity.

The porosity becomes lower after intense kneading. After 20 minutes of processing, a

porosity of 2 % was observed. The smaller pellets show lower porosities. The smaller pellets

are probably more susceptible to densification and deformation, while the larger pellets will

be more susceptible to deformation and break-up.

Decrease of the intragranular porosity is found in many different granulation processes.Pelletisatio

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