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You are on page 1of 48

Metropolitan Computing Corporation

East Hanover, New Jersey, USA

up, instrumentation, torque, power consumption.

Abstract:

Both high-shear and planetary mixers-granulators are routinely instrumented to

measure and record various process variables, most commonly, impeller torque

and motor power consumption. These variables provide information for end-point

determination, reproducibility, and scale-up. Illustrated by several case studies,

this article shows how to scale-up scientifically, using a dimensional analysis

approach, and offers practical considerations for practitioners in the field of wet

granulation.

Contents

List of Figures.............................................................................................................................. 2

List of Tables ............................................................................................................................... 3

INTRODUCTION ............................................................................................................................. 4

Current ........................................................................................................................................ 5

Voltage ........................................................................................................................................ 5

Capacitance ................................................................................................................................ 5

Conductivity................................................................................................................................. 6

Probe vibration ............................................................................................................................ 6

Boots Diosna Probe .................................................................................................................... 6

Chopper Speed ........................................................................................................................... 6

Impeller or Motor Shaft Speed .................................................................................................... 6

Motor Slip and Motor Load Analyzer........................................................................................... 6

Impeller Tip Speed ...................................................................................................................... 7

Relative Swept Volume ............................................................................................................... 7

Temperature................................................................................................................................ 7

Page 1 of 48

Binder Addition Rate ................................................................................................................... 7

Power Consumption................................................................................................................... 8

Impeller Torque ......................................................................................................................... 10

Torque Rheometer .................................................................................................................... 10

Reaction Torque........................................................................................................................ 11

Other possibilities...................................................................................................................... 11

Emerging Technology: Acoustic ................................................................................................ 11

Emerging Technology: Near Infra-Red (NIR) ............................................................................. 12

Emerging Technology: FBRM ................................................................................................... 12

END-POINT DETERMINATION.................................................................................................... 13

Torque vs. Power ...................................................................................................................... 13

Torque and Power Profiles........................................................................................................ 14

End-Point Optimization ............................................................................................................. 18

End-Point Reproducibility.......................................................................................................... 20

END-POINT SCALE-UP ............................................................................................................... 20

Scale-Up Attempts .................................................................................................................... 20

Dimensional Analysis ................................................................................................................ 21

Principle of Similitude................................................................................................................ 21

Dimensionless Numbers ........................................................................................................... 22

Comparison of attainable Froude Numbers .............................................................................. 23

-theorem (Buckingham).......................................................................................................... 24

Scientific scale-up procedure: ................................................................................................... 24

Relevance List........................................................................................................................... 24

Dimensional Matrix.................................................................................................................... 25

Case Study I: Leuenberger (1979,1983)................................................................................... 25

Case Study II: Landin et al. (1996) ........................................................................................... 29

Case Study III: Faure et al. (1998) ............................................................................................ 33

Case Study IV: Landin et al. (1999) .......................................................................................... 34

Case Study V: Faure et al. (1999) ............................................................................................ 35

Case Study VI: Hutin et al. (2004) ............................................................................................ 36

PRACTICAL CONSIDERATIONS FOR END-POINT DETERMINATION AND SCALE-UP ....... 38

LITERATURE REFERENCE......................................................................................................... 41

List of Figures

Fig. 1. Voltage, current, and power consumption of a typical mixer motor

Fig. 2. Schematic of a direct impeller torque transducer

Fig. 3. Impeller torque and motor power consumption for a small high shear

mixer

Fig. 4. A torque profile in a typical production batch

Fig. 5. Another batch by the same operator (power consumption profile)

Page 2 of 48

Fig. 6. A batch by a novice operator (power consumption profile)

Fig. 7. Another batch by inexperienced operator (torque profile)

Fig. 8. Wet granulation end-point as a factor in tableting optimization

Fig. 9. The range of Froude numbers for Collette Gral high-shear mixers.

Fig. 10. The range of Froude numbers for Fielder PMA high-shear mixers.

Fig. 11. Newton Power Number as a function of the Specific Amount of

Graqnulating Liquid (adapted from , Leuenberger and Sucker, 1979).

Fig. 12. Regression lines of the Newton Power Number on the product of Reynolds

number, Froude Number, and the length ratio for 3 different Fielder mixers

(from Landin et al., 1996).

Fig. 13. Regression graph of Case Study III.

Fig. 14. Regression graph of Case Study IV.

Fig. 15. Regression graph of Case Study V.

List of Tables

Table I. The Relevance List used by Leuenberger (1983)

Table II. The Dimensional Matrix for Case Study I

Table III. The Transformed Dimensional Matrix for Case Study I

Table IV: Dimensionless groups formed from the matrix in Table III

Table V. Relevance List for Case Study II (Landin et al., 1996)

Table VI. The Dimensional Matrix for Case Study II

Table VII. The Transformed Dimensional Matrix for Case Study II

Table VIII: Dimensionless groups formed from the matrix in Table VII

Table IX. Relevance list for Hutin et al. (2004)

Page 3 of 48

Introduction

Wet granulation is used mainly to improve flow and compressibility of powders,

and to prevent segregation of the blend components. Particle size of the

granulate is affected by the quantity and feeding rate of granulating liquid.

Wet massing in a high-shear mixing is frequently compared to fluid bed mixing

and to roller compaction technique (1), and the results seem to be formulation

dependent. Compared to high shear granulation, low shear or fluid bed process

requires less fluid binder, resulting in a shorter drying time, but also in a less

cohesive material (see, for example, 2, 3, or 4).

For excellent classical review of the wet granulation process, equipment and

variables, and measurement instruments available in the field, see papers by P.

Holm and his group (5-12). These papers have become a standard reference for

numerous subsequent publications.

Due to rapid densification and agglomeration that are caused by the shearing

and compressing action of the impeller in a high-shear single pot system, mixing,

granulation and wet massing can be done relatively quickly and efficiently. The

dangers lie in a possibility of overgranulation due to excessive wetting and

producing low porosity granules thus affecting the mechanical properties of the

tablets. As the liquid bridges between the particles are formed, granules are

subjected to coalescence alongside with some breakage of the bonds.

It stands to reason that mean granule size is strongly dependent on the specific

surface area of the excipients, as well as the moisture content and liquid

saturation of the agglomerate. During the wet massing stage, granules may

increase in size to a certain degree while the intragranular porosity goes down.

However, some heating and evaporation may also take place leading to a

subsequent decrease in the mean granule size, especially in small scale mixers.

Load on the main impeller is indicative of granule apparent viscosity and wet

mass consistency. It can be seen as an interplay of acceleration (direct impact of

the impeller), centrifugal, centripetal, and friction forces that act on the particles.

According to Cliff (13-14), binder addition rate controls granule density, while

impeller and chopper speed control granule size and granulation rate. The end-

point controls the mix consistency and reproducibility. Other factors that affect

the granule quality include spray position and spray nozzle type, and, of course,

the product composition. Such variables as mixing time and bowl or product

temperature are not independent factors in the process but rather are responses

of the primary factors listed above.

Page 4 of 48

What is an end-point?

End-point can be defined by the formulator as a target particle size mean or

distribution. Alternatively, the end-point can be defined in rheological terms. It

has been shown (15) that once you have reached the desired end-point, the

granule properties and the subsequent tablet properties are very similar

regardless of the granulation processing factors, such as impeller or chopper

speed or binder addition rate. I would call this the principle of equifinality.

The ultimate goal of any measurement in a granulation process is to estimate

viscosity and density of the granules, and, perhaps, to obtain an indication of the

particle size mean and distribution. One of the ways to obtain this information is

by measuring load on the main impeller.

Mixer instrumentation, in general, has numerous benefits. In addition to a

possible end-point determination, it can be used to troubleshoot the machine

performance (for example, help detect worn-out gears and pulleys or identify

mixing and binder irregularities). Instrumentation can serve as a tool for

formulation fingerprinting, assure batch reproducibility, aid in raw material

evaluation, process optimization and scale-up.

Granulator?

Current

Current in DC motors can be used as some indication of the load on the main

impeller because impeller torque is proportional to current in some intervals (13)

and therefore a current meter (ammeter) can be used for small scale direct

current (DC) motors. However, for alternating current (AC) motors (most often

used in modern mixers), there may be no significant change in current as motor

load varies up to 50% of full scale. At larger loads, current draw may increase

but this increase is not linearly related to load, and, consequently, current is

completely ineffective as a measurement of load. Moreover, current baseline

may shift with time.

Voltage

Voltage measurement generally has no relation to load.

Capacitance

Page 5 of 48

Capacitive sensor responds to moisture distribution and granule formation (16-

20). It provided similar end-points (based on the total voltage change) under

varying rates of agitation and liquid addition. Capacitive sensor can be threaded

into an existing thermocouple port for in-process monitoring.

Conductivity

Conductivity of the damp mass (21) makes it possible to quantify uniformity of

liquid distribution and packing density during wet massing time.

Probe vibration

Probe vibration analysis (22-23) require a specially constructed probe that

includes a target plate attached to an accelerometer (for in-process monitoring).

This measurement is based on the theory that increasing granule size results in

the increase of the acceleration of agglomerates striking the probe target. The

method has a potential for granulation monitoring and end-point control.

This probe (23) measured densification and increase of size of granules

(changes in momentum of granules moving with constant velocity due to a mass

change of the granules). The method did not gain popularity because of its

invasive nature.

Chopper Speed

Chopper speed has no significant effect on the mean granule size (5,6).

Rate of impeller rotation could be used as some indication of the work being

done on the material (24). Since the motor or impeller power consumption is

proportional to the product of torque and speed, the latter is an important factor in

evaluating the corresponding load.

Motor slip is the difference between rotational speed of an idle motor and motor

under load (25-26). Motor slip measurements, although relatively inexpensive,

do not offer advantages over the power consumption measurements. The

method did not gain popularity, probably because the slip is not linearly related to

load (27) despite some claims to the contrary.

Page 6 of 48

Impeller Tip Speed

Impeller tip speed corresponds to shear rate and has been used as a scale-up

parameter in fluid mixing (28). For processing of lactose granulations in Gral

mixers, however, it was shown by Horsthuis et al. (29) that the same tip speed

did not result in the same end-point (in terms of particle size distribution). These

findings were contradicted by other studies with Fielder mixers indicating that for

a constant tip speed successful scale-up is possible when liquid volume is

proportional to the batch size and wet massing time is related to the ratio of

impeller speeds (30).

Relative swept volume, that is, the volume swept by the impeller (and chopper)

per unit time, divided by the mixer volume, has been suggested as a scale-up

factor (11, 12, 31). This parameter is related to work done on the material and

was studied extensively at various blade angles (32). Higher swept volume leads

to higher temperature and denser granules. However, it was shown by Horsthuis

et al. (29) that the same relative swept volume did not result in the same end-

point (in terms of particle size distribution).

Temperature

Product and jacket temperature are usually measured by thermocouples. These

response variables are controlled by a variety of factors, notably, the speed of

the main impeller and the rate of binder addition.

There are conflicting reports on the preferred method of adding the binder. For

example, Holm (33) does not generally recommend adding dry binder to the mix (as

commonly done in order to avoid preparation of a binder solution) because a

homogeneity of binder distribution can not be assured. Others recommend just the

opposite (34-36).

Slow continuous addition of water (in case the water-soluble binder is dry mixed) or a

binder solution to the mix is a granulation method of choice (5, 6, 10-12, 37-40 and

many others). The granulating fluid should be added at a slow rate to avoid local

overwetting (34).

If the binder solution is added continuously, then the method of addition (pneumatic

or binary nozzle, atomization by pressure nozzle) should be considered in any end-

point determination and scale-up.

An alternative to a continuous binder liquid addition method is to add binder liquid all

at once (29) to assure ease of processing and reproducibility, reduce processing time

and to avoid wet mass densification that may occur during the liquid addition. This

Page 7 of 48

latter phenomenon may obscure the scale-up effect of any parameter under

investigation.

Power Consumption

One of the most popular and relatively inexpensive measurements is the power

consumption of the main mixer motor. It is measured by a watt transducer or a

power cell utilizing Hall effect (a measurable transversive voltage between the

two radial sides of a current conductor in a magnetic field, an effect discovered

by E.H. Hall in 1879).

Power consumption of the mixer motor for end-point determination and scale-up

is widely used [Leuenberger (40) and subsequent work, Holm (5) and

subsequent work; Landin et al. (41-44); Faure et al., (46-49); and many others

(16, 17, 20, 34, 36-40, 50-51)] because the measurement is economical, does

not require extensive mixer modifications and is well correlated with granule

growth.

Power consumption correlates with mean granule size of a granulation (8),

although the correlation is not always linear in the entire range. Intragranular

porosity also shows some correlation with power consumption (52). Normalized

work of granulation (power profile integrated over time) can accurately determine

end-points and is correlated well with properties granulates (53).

The main problem with power consumption measurements is that this variable

reflects load on the motor rather than load on the impeller. It relates to the

overall mixer performance, depends on motor efficiency and can change with

time regardless of the load.

Page 8 of 48

Fig. 1. Voltage, current, and power consumption of a typical mixer motor

power factor. In the range of interest, motor power consumption is generally

proportional to load on the motor and, to some degree, can reflect the load on the

impeller (Fig.1).

However, up to 30% of the power consumption of a motor can be attributed to

no-load losses due to windage (by cooling fan and air drag), friction in bearings,

and core losses that comprise hysteresis and eddy current losses in the motor

magnetic circuit. Load losses include stator and rotor losses (resistance of

materials used in the stator, rotor bars, magnetic steel circuit) and stray load

losses such as current losses in the windings (54).

Attempts to use a no-load (empty bowl, or dry mix) values as a baseline may be

confounded by a possible nonlinearity of friction losses with respect to load (55).

As the load increases, so does the current draw of the motor. This results in heat

generation that further impacts the power consumption (27). A simple test might

be to run an empty mixer for several hours and see if there is any the shift in the

baseline. Also, as the motor efficiency drops with age, the baseline most

definitely shifts over time.

Motor power consumption is non-linearly related to the power transmitted to the

shaft (56) and the degree of this non-linearity could only be guestimated.

Page 9 of 48

Impeller Torque

In a mixing process, changes in torque on the blades and power consumption of

the impeller occur as a result of change in the cohesive force or the tensile

strength of the agglomerates in the moistened powder bed.

shaft or on the coupling between the motor and impeller shaft (Fig.2). Since the

shaft is rotating, a device called slip ring is used to transmit the signal to the

stationary data acquisition system.

Planetary mixer instrumentation for direct torque measurement does not

substantially differ from that of a high shear mixer. Engineering design should

only take into account the planetary motion in addition to shaft rotation (57).

Impeller torque is an excellent in-line measure of the load on the main impeller

(52, 58).

Torque Rheometer

A torque rheometer is a device that provides an off-line measurement of torque

required to rotate the blades of the device and this torque can be used to assess

rheological properties of the granulation. It has been extensively used for end-

Page 10 of 48

point determination (41, 59-61). The torque values thus obtained were termed a

measure of wet mass consistency (46, 47, 62).

One of the main concerns is that using the torque value that the unit is reporting

instead of the dynamic viscosity for calculation of Reynolds numbers renders the

latter to become dimensional. Therefore, the Reynolds number calculated from

torque rheometer data is referred to as pseudo-Reynolds dimensional number.

Due to the fact that torque was shown to be proportional to a kinematic (rather

than dynamic) viscosity (63), it can have a conditional use in the dimensional

analysis of the process, as will be shown below.

Reaction Torque

By the third law of Newton, for every force there is a counter-force, collinear,

equal and opposite in direction. As the impeller shaft rotates, the motor tries to

rotate in the opposite direction, but it does not because it is bolted in place. The

tensions in the stationary motor base can be measured by a reaction torque

transducer.

Reaction torque is a less expensive alternative to direct impeller torque and is

recommended for mixers that have the motor and impeller shafts axially aligned

(in this case, the reaction torque is equal to direct torque and is opposite in sign).

Other possibilities

When the agglomeration process is progressing very rapidly, neither power

consumption nor torque on the impeller may be sensitive enough to adequately

reflect changes in the material. Some investigators feel that other measurements,

such as torque or force on the impeller blades may be better suited to monitor such

events.

There are other ideas floating around, for example, use of neural network to

describe and predict the behavior of the wet granulation (64) or control the end-

point by rapid image processing system (65).

A technique for measuring tensile strength of granules, in addition to power

consumption measurement, to facilitate optimal end-point determination was recently

described by Betz, Brgin and Leuenberger (50).

Powder flow patterns in wet granulation can be studied using positron emission

particle tracking (66). Eventually, this and similar techniques can be used to

validate various mathematical and statistical models of the process.

Applicability of piezo-electric acoustic emission sensors to end-point determination

have been studied since the beginning of this century (67). The technique is very

promising, especially since it is non-invasive, sensitive and relatively inexpensive.

Page 11 of 48

Granulation process signatures obtained with acoustic transducer can be used to

monitor changes in particle size, flow and compression properties (68, 69).

Use of a refractive NIR moisture sensor for end-point determination of wet

granulation was described by several authors (70, 71). There are technological

challenges associated with this approach, as the sensor can only measure the

amount of water at the powder surface.

Near infra-red monitoring of granulation process was attempted by researchers at

many major pharmaceutical corporations with a modest success. In particular, yet

unpublished work by David Rudd of GlaxoSmithKline in England should be

mentioned as a part of the global effort in the field of Process Analytical Technology

(PAT).

Focused Beam Reflectance Measurement (FBRM) is a particle size

determination technique based on a laser beam focusing in the vicinity of a

sapphire window of a probe. The beam follows a circular path at speeds of up to

6 m/s. When it intersects with the edge of a particle passing by a window surface,

an optical collector records a backscatter signal. The time interval of the signal

multiplied by the beam speed represents a chord length between two points on

the edge of a particle. The chord length distribution (CLD) can be recalculated to

represent either a number or volume weighted particle size distribution.

in many cases, where precision is more important than accuracy, CLD

measurements are adequate to monitor dynamic changes in process parameters

related to particle size and shape, concentration, and rheology of fluid

suspensions

Several attempts were made to evaluate the use of FBRM particle size analyzer as a

potential tool for granulation end-point determination (72). Dilworth et al. (73) have

compared power consumption, FBRM and acoustic signals in a study of a wet

granulation process in Fielder PMA 200 mixer. It was found that these techniques

were complimentary, with FBRM probe capable to follow median granule size

growth even when the power consumption curve showed a plateau.

A major disadvantage of the FBRM method is that measured CLD does not

directly represent a particle size distribution (PSD). Conversion of CLD to PSD

is not straightforward and requires sophisticated mathematical software that is

not easy to validate. Moreover, CLD depends on optical properties and shape of

the particles, as well as the focal point position. The total number of counts

measured is a function both of solids concentration and probe location.

Page 12 of 48

End-Point Determination

End-point detection in wet granulation has become a major scientific and

technological challenge (74). Monitoring granulation is most commonly achieved

by collecting either power or torque signals, or both. In what follows, we will

compare both methods.

When we say power consumption, we usually refer to the main motor. It reflects the

load on the motor due to useful work, as well as the power needed to run the motor

itself (losses due to eddy currents, friction in couplings, etc.).

It is quite possible (and, indeed, quite pertinent) to talk about the power consumption

of the impeller, which is, obviously, quantitatively less than the power consumption of

the motor and relates directly to the load on the impeller.

Power ~ Torque * Speed

Impeller power consumption can be calculated as a product of the direct torque,

rotational impeller speed, and a coefficient (usually equal to 2 times a unit

conversion factor, if required).

The power consumption of the mixer motor differs from that of the impeller by the

variable amount of power draw imposed by various sources (mixer condition,

transmission, gears, couplings, motor condition, etc.)

Compared to impeller torque, motor power consumption is easier to measure;

watt meters are inexpensive and can be installed with almost no downtime.

However, motor power signal may not be sensitive enough for specific products or

processing conditions. Wear and tear of mixer and motor may cause power

fluctuations. Moreover, power baseline may shift with load.

Impeller torque, on the other hand, is closer to where the action is, and is directly

related to the load on the impeller. Torque is not affected by mixer condition.

Although the motor power consumption is strongly correlated with the torque on the

impeller (38), it is less sensitive to high frequency oscillations caused by direct impact

of particles on the blades as evidenced by FFT technique (16).

Power consumption or torque fluctuations are influenced by granule properties

(particle size distribution, shape index, apparent density) and the granulation time.

Fluctuation of torque / power consumption and intensity of spectrum obtained by FFT

analysis can be used for end-point determination (37).

It was observed that when the end-point region of a granulation is reached, the

frequency distribution of a power consumption signal reaches a steady state (75). It

should be repeated here that torque shows more sensitivity to high frequency

oscillations.

Page 13 of 48

Torque and Power Profiles

Fig. 3. Impeller torque and motor power consumption for a small high shear

mixer (Fielder PMA 10).

Fig. 3 illustrates the classical power and torque profiles that start with a dry mixing

stage, rise steeply with binder solution addition, level off into a plateau, and then

exhibit overgranulation stage. The power and torque signals have similar shape and

are strongly correlated. The pattern shows a plateau region where power

consumption or torque is relatively stable.

The peak of the derivative indicates the inflection point of the signal. Based on the

theory by Leuenberger (1979 and subsequent work), useable granulates can be

obtained in the region that starts from the peak of the signal derivative with respect to

time and extends well into the plateau area (40). Prior to the inflection point, a

continuous binder solution addition may require variable quantities of liquid. After

that point, the process is well defined and the amount of binder solution required to

reach a desired end-point may be more or less constant.

Torque or power consumption pattern of a mixer is a function of the viscosity of both

the granulate and binder. With the increasing viscosity, the plateau is shortened and

sometimes vanishes completely thereby increasing the need to stop the mixer at the

exact end-point.

At low impeller speeds or high liquid addition rates, the classic S-shape of the power

consumption curve may become distorted with a steep rise leading into

overgranulation (9).

Page 14 of 48

The area under the torque-time curve is related to the energy of mixing and can be

used as an end-point parameter. Area under power consumption curve divided by

the load gives the specific energy consumed by the granulation process. This

quantity is well correlated with the relative swept volume (11, 12, 32).

The consumed energy is completely converted into heat of the wet mass (7), so that

the temperature rise during mixing shows some correlation with relative swept

volume and Froude number (29) that relates the inertial stress to the gravitational

force per unit area acting on the material.

Fig. 4 represents a record of a typical granulation batch done by an experienced

operator on large Hobart mixer. You can see that the batch was stopped on the

downslope of the derivative.

Page 15 of 48

Fig. 5. Another batch by the same operator (power consumption profile)

On a Fig. 5 you can see another batch made by the same operator. This time it is a

power consumption trace, but again it extends beyond the peak of the derivative and

the end-point thus can be deemed reproducible.

Page 16 of 48

Fig.6. A batch by a novice operator (power consumption profile)

In the batch represented in Fig. 6, a novice operator trainee has stopped the batch

well before the peak of the derivative. This required a major adjustment of the

tableting operation (force and speed) to produce tablets in an acceptable range of

material properties (hardness and friability).

Page 17 of 48

Fig. 7. Another batch by inexperienced operator (torque profile)

In this batch (Fig. 7), the same novice operator has stopped the granulation process,

opened the lid, took a sample, and decided to granulate for another 10 seconds. You

can see that there is no indication that the peak of the derivative was reached at the

end-point.

Thus, it seems that monitoring torque or power can fingerprint not only the product,

but the process and the operators as well.

A number of publications relate to practical experience of operators on the production

floor (34, 76-78).

End-Point Optimization

Page 18 of 48

Fig. 8. Wet granulation end-point as a factor in tableting optimization

Agglomeration of particles in wet granulation have been studied extensively (24, 79).

The optimal end-point can be thought of as the factor affecting a number of

agglomerate properties (Fig.8).

With so many variables involved in a granulation process, it is no wonder that more

and more researchers throw in a number of factors together in an attempt to arrive at

an optimum response (30, 35, 80-88).

The final goal of any granulation process is a solid dosage form, such as tablets.

Therefore, when optimizing a granulation process, the list of factors affecting tablet

properties may include both the granulation end-point and the tableting processing

parameters, such as compression force or tablet press speed.

In one of the most interesting works based on the experimental design approach, an

attempt was made to find a statistical relationship between the major factors affecting

both granulation and compaction, namely, granulation end-point, press speed (dwell

time), and compression force (88). The resulting equation allowed optimization of

such standard response parameters as tablet hardness, friability and disintegration

time. This study has also investigated the possibility of adjusting the tableting

parameters in order to account for an inherent variability of a wet granulation

process.

Multivariate optimization of wet granulation may include hardness, disintegration and

ejection as response variables (89). Compressibility property of granulations is

extremely sensitive to various processing parameters of wet granulation (90).

Page 19 of 48

Recently, the experimental design procedure was applied to low shear wet

granulation (91) with a factorial design used to evaluate the influence of such

factors as binder strength and agitator speed.

End-Point Reproducibility

As will be shown in the next section, for every blend and a fixed set of values for

processing factors (such as mixer geometry, blade speed, powder volume,

amount and method of addition of granulating liquid), a wet granulation process

state (end-point) is completely characterized by rheological properties of the wet

mass (density, viscosity), which are, in turn, a function of particle size, shape and

other properties. The process can be quantified with the help of dimensionless

Newton Power Number Np that will assume a certain numerical value for every

state (condition) of the granulate. Under fixed processing conditions, Np will be

proportional to Net Power Consumption P for any end-point (defined, in part, by

wet mass density). Thus, in order to reproduce an end-point, it is sometimes

sufficient to monitor power of the impeller (or the motor) and stop when a

predefined net level of the signal is reached. If, however, any of the processing

variables or the rheological definition of the end-point has changed, a more

sophisticated approach is required, as described below.

End-Point Scale-Up

Scale-Up Attempts

Numerous studies were undertaken in an attempt to determine empirically (and,

lately, with a solid theoretical foundation) useful scale-up parameters of the wet

granulation process (e.g., 46, 87, 92).

In a seminal and elegant work published in 1993, Horsthuis and his colleagues from

Organon in The Netherlands have studied granulation process in Gral mixers of 10,

75, and 300 liter size (29). Comparing relative swept volume, blade tip speed and

Froude numbers with respect to end-point determination (as expressed by the time

after which there is no detectable change in particle size), they have concluded that

only constant Froude numbers result in a comparable end-point.

In another attempt to determine good scale-up parameters, the University of

Maryland group under the direction of Dr. Larry Augsburger (30) has applied the

ideas of Leuenberger and Horsthuis to show that, for a specific material, end-point

can be expressed in terms of wet massing time. For a constant ratio of a binder

volume to a batch size, this factor was found to be inversely proportional to impeller

speed when the impeller tip speed was held constant for all batches. However, this

result was not corroborated by other studies or other materials.

Yet another example of semi-empirical scale-up effort (93) was based on the fact that

normalized power profiles are very similar and allow for direct comparison of different

Page 20 of 48

size granulators, at least for the equipment and materials used in the study.

Normalized power curve rose at a relatively constant rate in the region where the

ratio of water to dry mass is 0.1 - 0.2 (slope plateau). Despite a rapid increase in the

slope of the power curve, the desired end-point was still detectable at a moment

when the slope of power consumption signal exceeded the plateau level by a factor

of 5 (empirical observation). Using this approach, an acceptable end-point (target

particle size of 135 microns) was first established on a 10 liter Fielder and then

scaled to 65 liter Fielder and 250 liter Diosna.

Dimensional Analysis

A rational approach to scale-up using dimensional analysis has been in use in

chemical engineering for quite some time. This approach, based on the use of

process similarities between different scales, was being applied to pharmaceutical

granulation since the early work of Hans Leuenberger in 1979 (40).

Dimensional analysis is a method for producing dimensionless numbers that

completely describe the process. The analysis should be carried out before the

measurements are made because dimensionless numbers essentially condense the

frame in which the measurements are performed and evaluated. The method can be

applied even when the equations governing the process are not known. Dimensional

analytical procedure was first proposed by Lord Rayleigh in 1915 (94).

Principle of Similitude

Imagine that you have successfully scaled up from a 10 liter batch to 300 liter batch.

What exactly happened? You may say: I got lucky. Apart from luck, there had to

be similarity in the processing and the end-point conditions of the wet mass of the

two batches.

According to the modeling theory, two processes may be considered similar if there

is a geometrical, kinematic and dynamic similarity (95).

Two systems are called geometrically similar if they have the same ratio of

characteristic linear dimensions. For example, two cylindrical mixing vessels are

geometrically similar if they have the same ratio of height to diameter.

Two geometrically similar systems are called kinematically similar if they have the

same ratio of velocities between corresponding system points. Two kinematically

similar systems are dynamically similar when they have the same ratio of forces

between corresponding points. Dynamic similitude for wet granulation would imply

that the wet mass flow patterns in the bowl are similar.

The gist of dimensionless analysis is as follows: For any two dynamically similar

systems, all the dimensionless numbers necessary to describe the process have the

same numerical value (96). Once a process is expressed in terms of dimensionless

variables, we are magically transferred in a world where there is no space and no

time. Therefore, there is no scale and, consequently, there are no scale-up problems.

The process is characterized solely by numerical values of the dimensionless

Page 21 of 48

variables (numbers). In other words, dimensionless representation of the process is

scale-invariant.

Lack of geometrical similarity often is the main obstacle in applying the Dimensional

Analysis to solving the scale-up problems. It was shown, for example, that Collette

Gral 10, 75 and 300 are not geometrically similar (29). In such cases, a proper

correction to the resulting equations is required.

Dimensionless Numbers

Dimensionless numbers most commonly used to describe wet granulation

process are Newton, Froude and Reynolds:

Fr = n2 d / g Froude

Re = d n /

2

Reynolds

(for list of symbols, notation and dimensions, see Appendix).

Newton (power) number, which relates the drag force acting on a unit area of the

impeller and the inertial stress, represents a measure of power requirement to

overcome friction in fluid flow in a stirred reactor. In mixer-granulation applications,

this number can be calculated from the power consumption of the impeller or

estimated from the power consumption of the motor.

Froude Number (96) has been described for powder blending and was suggested as

a criterion for dynamic similarity and a scale-up parameter in wet granulation (29).

The mechanics of the phenomenon was described as interplay of the centrifugal

force (pushing the particles against the mixer wall) and the centripetal force produced

by the wall, creating a compaction zone.

Reynolds numbers relate the inertial force to the viscous force (97). They are

frequently used to describe mixing processes and viscous flow, especially in

chemical engineering (98).

We have seen that there exists sort of a principle of equifinality that states: An end-

point is an end-point is and end-point, no matter how it was obtained. Different

processing pathways can lead to different end-points, each with its own set of

granulation properties. However, once an end-point is reached, it is characterized by

certain numerical values of the dimensionless variables describing the process, and

these values will be independent of scale.

At the same end-point, no matter how defined, the rheological and dimensional

properties of the granules are similar. As we will see from the examples described

below, that means that the density and dynamic viscosity of the wet mass are

constant, and the only variables that are left are the process variables, namely batch

mass, impeller diameter and speed, and the geometry of the vessel.

Page 22 of 48

Comparison of attainable Froude Numbers

Horsthuis et al. (29) showed that an end-point can be reproduced and scaled up in

Gral mixers by keeping the Froude numbers constant. For the same end-point, in

dynamically similar mixers (same geometrical ratios, same flow patterns), all

dimensionless numbers describing the system should have the same numerical

value, but Froude numbers for any mixer are easiest to compute.

Fig. 9. The range of Froude numbers for Collette Gral high-shear mixers.

Each mixer has a range of attainable Froude numbers, and an end-point transfer

between mixers can only be achieved when such ranges overlap. Fig. 9 represents

such a range for Collette Gral mixers. It can be seen that Gral 10 and Gral 150 has

no overlap of Froude number ranges, and therefore a direct scale-up is not possible

(in addition, Gral mixers are not exactly similar geometrically, as was stated

elsewhere).

The range of Froude numbers for Fielder PMA series mixers is shown on Fig. 10.

The 10 liter laboratory scale mixer at its lowest speed settings can reach the Froude

numbers of all other mixers, except one. These considerations can be useful for

planning a scale-up or technology transfer operation.

Page 23 of 48

Fig. 10. The range of Froude numbers for Fielder PMA high-shear mixers.

-theorem (Buckingham)

Every physical relationship between n dimensional variables and constants

(x0, x1, x2, , xn) =0

can be reduced to a relationship

(0 ,1, , m) = 0

between m = n - r mutually independent dimensionless groups,

where r = number of dimensional units, i.e. fundamental units (rank of the

dimensional matrix).

1. Describe the process using a complete set of dimensionless numbers, and

2. Match these numbers at different scales.

The dimensionless space in which the measurements are presented or measured

will make the process scale invariant.

Relevance List

Page 24 of 48

The dimensional analysis starts with a list of all variables thought to be important for

the process being analyzed (the so-called relevance list).

To set up a relevance list for any process, one needs to compile a complete set of all

relevant and mutually independent variables and constants that affect the process.

The word complete is crucial here. All entries in the list can be subdivided into

geometric, physical and operational. Each relevance list should include only one

target (dependent response) variable.

Many pitfalls of dimensional analysis are associated with the selection of the

reference list, target variable, or measurement errors (e.g. when friction losses are of

the same order of magnitude as the power consumption of the motor). The larger the

scale-up factor, the more precise the measurements of the smaller scale have to be

(96).

Dimensional Matrix

Dimensional analysis can be simplified by arranging all relevant variables from the

relevance list in a matrix form, with a subsequent transformation yielding the required

dimensionless numbers. The dimensional matrix consists of a square core matrix

and a residual matrix (you will see examples in the Case Studies below).

The rows of the matrix consist of the basic dimensions, while the columns represent

the physical quantities from the relevance list. The most important physical properties

and process-related parameters, as well as the target variable (that is, the one we

would like to predict on the basis of other variables) are placed in one of the columns

of the residual matrix.

The core matrix is then linearly transformed into a matrix of unity where the main

diagonal consists only of ones and the remaining elements are all zero. The

dimensionless numbers are then created as a ratio of the residual matrix and the

core matrix with the exponents indicated in the residual matrix. This rather simple

process will be illustrated below in the examples.

This example is based on the ground-breaking studies conducted by Hans

Leuenberger at the University of Basel and Sandoz AG (40, 100-103).

Quantity Symbol Units Dimensions

1 Power consumption P Watt M L2 T-3

2 Specific density kg / m3 M L-3

3 Blade diameter d m L

Page 25 of 48

4 Blade velocity n rev / s T-1

5 Binder amount s kg M

6 Bowl volume Vb m3 L3

7 Gravitational g m / s2 L T-2

constant

8 Bowl height H m L

The Relevance List in Table I reflects certain assumptions used to simplify the model,

namely, that there are short range interactions only and no viscosity factor (and

therefore, no Reynolds number).

Why do we have to consider the gravitational constant? Well, imagine the same

process to be done on the moon - would you expect any difference?

One target variable (Power consumption) and 7 process variables / constants thus

represent the number n=8 of the -theorem. The number of basic dimensions r = 3

(M, L, and T). According to the theorem, the process can be reduced to relationship

between m = n - r = 8 3 = 5 mutually independent dimensionless groups.

Core matrix Residual Matrix

d n P s Vb g H

Mass [M] 1 0 0 1 1 0 0 0

Length [L] 3 1 0 2 0 3 1 1

Time [T] 0 0 1 3 0 0 -2 0

The Dimensional Matrix in Table II was constructed as described above, with the

rows listing the basic dimensions and the columns indicating the physical quantities

from the relevance list.

Unity matrix Residual Matrix

d n P s Vb g H

M 1 0 0 1 1 0 0 0

3M + L 0 1 0 5 3 3 1 1

-T 0 0 1 3 0 0 2 0

Page 26 of 48

Transformation of the Dimensional Matrix (Table III) into a unity matrix is

straightforward. To transform -3 in L-row / -column into zero, one linear

transformation is required. The subsequent multiplication of the T-row by 1 transfers

the -1 of the n-column to +1.

The 5 dimensionless groups are formed from the 5 columns of the residual matrix by

dividing each element of the residual matrix by the column headers of the unity

matrix, with the exponents indicated in the residual matrix.

The residual matrix contains five columns; therefore five dimensionless groups

(numbers) will be formed (Table IV).

Table IV: Dimensionless groups formed from the matrix in Table III.

Expression Definition

group

0 = P / (1 * d5 * n3) = Np Newton (Power) number

1 = s / (1 * d3 * n0) ~ q t / (Vp) Specific Amount of Liquid

Vp Volume of particles

q = binder addition rate

t = binder addition time

2 = Vb / (0 * d3 * n0) ~ (Vp / Vb)-1 Fractional Particle Volume

3 = g / (0 * d1 * n2) = Fr-1 Froude Number

4 = H / (0 * d1 * n0) =H/d Ratio of Lengths

0 = f (1, 2, 3, 4).

Assuming that the groups 2, 3, 4 are essentially constant, the -space can be

reduced to a simple relationship 0 = f (1), that is, the value of Newton number Np at

any point in the process is a function of the specific amount of granulating liquid.

Up to this point, all the considerations were rather theoretical. From the theory of

modeling, we know that the above dimensional groups are functionally related. The

form of this functional relationship f, however, can be established only through

experiments.

Leuenberger and his group have empirically established that the characteristic (that

is, relative to the batch size) amount of binder liquid required to reach a desired end-

point (as expressed by the absolute value of Np and, by proxy, in terms of Net Power

Consumption P) is scale-up invariable, that is, independent of the batch size (Fig.

Page 27 of 48

11), thus specifying the functional dependence f and establishing rational basis for

granulation scale-up.

Quantity (adapted from Bier, Leuenberger and Sucker, 1979, ref. 40).

Experiments with 5 different planetary mixers with batch sizes ranging from 3.75 kg

up to 60 kg showed that, if the binder is mixed in as a dry powder and then liquid is

added at a constant rate proportional to the batch size, the ratio of granulation

liquid quantity to a batch size is constant. This was shown for non-viscous binders.

The ratio of quantity of granulating liquid to batch size at the inflection point of power

vs. time curve is constant irrespective of batch size and type of machine. Moreover,

for a constant rate of low viscosity binder addition proportional to the batch size, the

rate of change (slope or time derivative) of torque or power consumption curve is

linearly related to the batch size for a wide spectrum of high shear and planetary

mixers. In other words, the process end-point, as determined in a certain region of

the curve, is a practically proven scale-up parameter for moving the product from

laboratory to production mixers of different sizes and manufacturers.

As we have indicated before, for any desired end-point, the power consumption will

be proportional to the Newton power number, at a constant mixer speed.

The Leuenbergers ideas relating to the use of power consumption for wet

granulation end-point determination were tested and implemented by numerous

researchers [e.g., (9, 20, 34, 39, 40).

In 2001, Holm, Schaefer and Larsen (74) have applied the Leuenberger method

to study various processing factors and their effect on the correlation between

power consumption and granule growth. They have found that such a correlation

did indeed exist but was dependent, as expected, on the impeller design, the

Page 28 of 48

impeller speed, and the type of binder. The conclusion was that it was possible to

control the liquid addition by the level detection method whereby the liquid

addition is stopped at a predetermined level of power consumption. An

alternative approach involves an inflection point (peak of signal derivative with

respect to time).

Different vessel and blade geometry will contribute to the differences in absolute

values of the signals. However, the signal profile of a given granulate composition in

a high shear mixer is very similar to one obtained in a planetary mixer.

For accuracy, in power number Np calculations, the power of the load on the impeller

rather than the mixer motor should be used. Before attempting to use dimensional

analysis, one has to measure / estimate power losses for empty bowl or dry stage

mixing. Unlike power consumption of the impeller (based on torque measurements),

the baseline for motor power consumption does not stay constant and changes

significantly with load on the impeller, mixer condition or motor efficiency. This may

present inherent difficulties in using power meters instead of torque. Torque, of

course, is directly proportional to power drawn by the impeller (the power number can

be determined from the torque and speed measurements) and has a relatively

constant baseline.

Scale-up in fixed bowl mixer-granulators has been studied by Ray Rowe and Mike

Cliffs group (42) using the classical dimensionless numbers of Newton (Power),

Reynolds and Froude to predict end-point in geometrically similar high-shear Fielder

PMA 25, 100, and 600 liter machines.

Quantity Symbol Units Dimensions

1 Power consumption P Watt M L2 T-3

2 Specific density kg / m3 M L-3

3 Blade diameter D m L

4 Blade speed n rev / s T-1

5 Dynamic viscosity Pa * s M L-1 T-1

6 Gravitational g m / s2 L T-2

constant

7 Bowl height H m L

Page 29 of 48

The relevance list (Table V) included power consumption of the impeller (as a

response) and six factor quantities: impeller diameter, impeller speed, vessel height,

specific density and dynamic viscosity of the wet mass, and the gravitational

constant.

Note that dynamic viscosity has replaced the binder amount and bowl volume of the

Leuenbergers relevance list, thus making it applicable to viscous binders and

allowing long range particle interactions responsible for friction.

Core matrix Residual Matrix

d n P g H

Mass M 1 0 0 1 1 0 0

Length L 3 1 0 2 -1 1 1

Time T 0 0 1 3 -1 -2 0

The dimensional matrix for Case Study II (Table VI) is different from Table II: the

columns for mass [M] and bowl volume [L3] are replaced by a viscosity [ML-1T-1]

column. Evidently, it was assumed that the mass and volume can be adequately

represented in the Relevance List by the density and powder height in a semi-

cylindrical vessel of a known diameter.

d n P g H

M 1 0 0 1 1 0 0

3M + L 0 1 0 5 2 1 1

-T 0 0 1 3 1 2 0

Table VII. The Transformed Dimensional Matrix for Case Study II.

The residual matrix (Table VII) contains four columns, therefore four dimensionless

groups (numbers) will be formed, in accordance with the -theorem (7 variables 3

dimensions = 4 dimensionless groups).

Table VIII: Dimensionless groups formed from the matrix in Table VII

group Expression Definition

Page 30 of 48

0 = P / (r1 * d5 * n3) = Np Newton (Power) number

2 = g / (r0 * d1 * n2) = Fr-1 Froude number

3 = H / (r0 * d1 * n0) =H/d Geometric number (Ratio of

Characteristic Lengths)

Table VIII lists the resulting groups; they correspond to Newton power, Reynolds,

and Froude numbers, and the ratio of characteristic lengths.

Under the assumed condition of dynamic similarity, from the dimensional analysis

theory, it follows that 0 = (1, 2, 3,), and, therefore, Np = (Re, Fr, H/d).

When corrections for gross vortexing, geometric dissimilarities, and powder bed

height variation were made, data from all mixers (Fielder PMA 25, 100 and 600 Liter)

correlated to the extent that allows predictions of optimum end-point conditions. The

linear regression of Newton Number (power) on the product of adjusted Reynolds

Number, Froude Number and the Geometric number (in log/log domain) yields [Fig.

12] an equation of the form:

Log10 Np = a log10 (Re Fr H / d) + b

where b = 796 and a = - 0.732.

Theoretically, in such a representation of the granulation process, a slope a= -1

would signify a true laminar flow whereby a slope significantly less than -1 or

approaching 0 would indicate turbulence. Thus, one would expect planetary mixers

to have a slope closer to -1 compared to that of high shear granulators. However, the

results described here and in subsequent studies do not show a clear difference

between slopes of regression for planetary and high shear mixers.

Page 31 of 48

Fig. 12. Regression lines of the Newton Power Number on the product of

Reynolds number, Froude Number, and the length ratio for 3 different Fielder

mixers (from Landin et al., 1996, ref. 42).*

* Reprinted from Int J Pharm, Vol 134, Landin M, York P, Cliff MJ, Rowe RC, Wigmore AJ. The

effect of batch size on scale-up of pharmaceutical granulation in a fixed bowl mixer-granulator,

Pages 243-246, Copyright 1996, with permission from Elsevier".

However, the correlation coefficient of 0.7854 for the final curve fitting effort indicates

the presence of many unexplained outlier points. One of the possible concerns was

an inherent error in measuring the height of the powder bed from the wet mass

density.

In a subsequent communication (43) it was shown that, in order to maintain

geometric similarity, it is important to keep the batch size proportional to the bowl

shape.

Another concern is interpretation of data from mixer torque rheometer that was used

to assess the viscosity of wet granulation. The torque values obtained from the

rheometer were labeled wet mass consistency and were used instead of dynamic

viscosity to calculate Reynolds numbers. It was shown (41, 62) that such torque

values are proportional to kinematic viscosity = / rather than dynamic viscosity

required to compute Reynolds numbers. The degree of proportionality between

and was found to be formulation dependent.

Consequently, it was prudent to acknowledge that the above regression equation is

not dimensionless because for all practical purposes, the Reynolds number Re was

replaced by Re, what the authors called a pseudo Reynolds number with the

dimensions [L-3 T]. This predicament did not deter a plethora of other studies in the

same line of reasoning to be published in recent years. Note that this pseudo

Reynolds number has a physical meaning: it is a reciprocal of volumetric flow

rate.

Page 32 of 48

Case Study III: Faure et al. (1998)

The same approach was applied to planetary Hobart AE240 mixer with two

interchangeable bowls, 5 and 8.5 liters (45). Assuming the absence of chemical

reaction and heat transfer, the following relevance list for the wet granulation process

was suggested (Table VIII):

Table IX. Relevance List for Case Study III (Faure et al., 1998)

Quantity Symbol Units Dimensions

1 Net Power P Watt M L2 T-3

2 Wet mass bulk or specific density kg / m3 M L-3

3 Impeller radius (or diameter) d m L

4 Impeller speed n rev / s T-1

5 Granulation dynamic viscosity Pa * s M L-1 T-1

6 Gravitational constant g m / s2 L T-2

7 Height of granulation bed in the bowl h m L

One difference from Table V of the previous study is the use of Net Power P that

was defined as motor power consumption under load minus the dry blending

baseline level.

An assumption was made that a motor drive speed is proportional to the impeller

blade speed. Another consideration was that the ratio of characteristic lengths h/d is

proportional to (and, therefore, can be replaced by) a fill ratio Vm / Vb, which was, in

turn, shown to be proportional to (and therefore could be replaced in the final

equation by) the quantity m / ( d3). This is a preferred method of representing a fill

ratio because the wet mass m is easier to measure than the height of the granulation

bed in the bowl.

Dimensional analysis and application of the Buckingham theorem lead to four

dimensionless quantities that adequately describe the process: Ne, Re, Fr, and h/d

As before, a relationship of the form

b a

Np = 10 (Re Fr Rb 3 / m) , or

Log10 Np = a log10 (Re Fr Rb 3 / m) + b

was postulated and the constants a and b (slope and intercept in a log-log domain)

were found empirically (b = 2.46 and a = - 0.872) with a good correlation (>0.92)

between the observed and predicted numbers (Fig. 13). Radius of the bowl Rb

cubed was used to represent the bowl volume Vb. The graph indicates a collection of

end-points produces with different mixers and different processing factors.

Page 33 of 48

It was noted that the above equation can be interpreted to indicate that

P ~ d2 Vm / Vb,

that is, that the net power consumption of the impeller varies directly with the fill ratio,

wet mass viscosity and the surface swept by the blades (~ d2).

Fig. 13. Regression graph of Case Study III. The Reynolds Number Re was, in fact, a

dimensional pseudo Reynolds number Re. Data from a dual bowl Hobart

AE240 planetary mixer (ref. 45).

Reproduced from Faure A, Grimsey IM, Rowe RC, York P, Cliff MJ. A methodology for the optimization

of wet granulation in a model planetary mixer. Pharm Dev Tech 3(3):413-422, 1998

Wet masses produced at the same end-point (regardless of bowl and batch size,

impeller speed, and moisture content) have been consistently shown to result in

the same final dry granule size distribution, bulk density, flow and mechanical

strength.

Following the methodology developed in the previous Case Study using the same

assumptions, this study was also performed on planetary mixers Collette MP20,

MP90, and MPH 200 (44). The relevance list and dimensional matrix were the same

as before, and torque measurements from torque rheometer were again used to

represent kinematic viscosity (instead of dynamic viscosity) in Reynold numbers.

Fig. 14 represents the resulting regression line

Page 34 of 48

Log10 Np = a log10 (Re Fr Rb 3 / m) + b

for the combined results from three mixers with bowl sizes 20, 90, and 200 liters

showed a pretty good fit to data (r2 > 0.95). The values for the slope and intercept

were found to be: a = - 0.68, b = 1280. Data from two other mixers with bowl sizes 5

and 40 liter produces lines that were significantly different from the first set of mixers.

The authors explained this difference by an assumption of different flow patterns in

the two groups of mixers.

Fig. 14. Regression graph of Case Study IV. The Reynolds Number Re was, in fact,

a dimensional pseudo Reynolds number Re.* Data from Collette MP20,

MP90, and MPH 200 planetary mixers (ref. 44).

*Reproduced from Landin M, York P, Cliff MJ, Rowe RC. Scaleup of a pharmaceutical granulation

in planetary mixers. Pharm Dev Technol, 4(2):145-150, 1999

This study was done on Collette Gral Mixers (8, 25, 75 and 600 Liter) and followed

the accepted and by now, standard - methodology developed earlier (48). The

problem with the scale-up in the Gral mixers was the lack of geometric similitude:

there was significant distortion factor between the bowl geometries at different

scales. In addition, the researchers had to take into account the lack of dynamic

similitude due to different wall adhesion and lid interference that was partially relieved

by using a PolyTetraFluoroEthylene (PTFE) lining.

Page 35 of 48

The end result of the dimensional analysis and experimental work was, again, a

regression equation (Fig. 15) of the form

Log10 Np = a log10 (Re Fr Rb 3 / m) + b

The regression coefficient was r2 > 0.88 using the data from the 8, 25 and 75 liter

bowls with PTFE lining, and the 600 liter bowl that did not require the lining. The

slope was found to be a = -0.926, and the intercept b = 3.758.

Fig. 15. Regression graph of Case Study V.* Data from Collette Gral 8, 25, 75 and

600 liter mixer-granulators (ref.48).

* Reprinted from Eur J Pharm Sci, Vol. 8(2), Faure A, Grimsey IM, Rowe RC,

York P, Cliff MJ. Applicability of a scale-up methodology for wet granulation

processes in Collette Gral high shear mixer-granulators, pages 85-93, Copyright

1999, with permission from Elsevier.

In this study, the foregoing methodology of dimensional analysis was applied to a

kneading process of drug - cyclodextrin complexation (104). Aoustin kneader

with dual Z blades was instrumented for torque measurements and multiple runs

were made at 2 scales (2.5 and 5 Liter).

The Relevance List for this study (Table IX) differs from those discussed previously

by addition of blade length as one of the crucial factors affecting the process.

Page 36 of 48

Table IX. Relevance list for Hutin et al. (2004)

Quantity Symbol Units Dimensions

1 Power consumption P Watt M L2 T-3

2 Specific density kg / m3 M L-3

3 Blade radius d M L

4 Blade speed n rev / s T-1

5 Dynamic viscosity Pa * s M L-1 T-1

6 Gravitational constant g m / s2 L T-2

7 Powder bed height h M L

8 Blade length l M L

Introduction of the blade length, after the proper operations with the dimensional

matrix, creates another dimensionless quantity, namely, d / l, so that the resulting

regression equation has the form of

-a

Np = b ( Re * Fr * h / d * d / l ))

Experiments showed that the model fits data remarkably well (r2 > 0.99).

Unfortunately, the Pharmaceutical Technology journal does not grant permissions to

reproduce individual graphs; therefore an interested reader is referred to the source

article to see the regression lines from this study.

Page 37 of 48

Practical Considerations for End-Point

Determination and Scale-Up

How to determine an end-point?

A wet granulation end-point should be defined empirically in terms of wet mass

density and viscosity, particle size distribution, flowability or tableting parameters

(e.g., capping compression).

It is advisable to run a trial batch at a fixed speed and with a predetermined

method of binder addition (for example, add water continuously at a fixed rate to

a dry mix with a water-soluble binding agent).

Before adding the liquid, measure the baseline level of motor power consumption

Po or impeller torque o at the dry mix stage.

During the batch, stop the process frequently times to take samples and, for each

sample, note the end-point values of power consumption Pe or impeller torque e.

For each of these end-points, measure the resulting wet mass density . As a

result, you will be able to obtain some data that will relate the end-point

parameters listed above with the processing variables in terms of net motor

power consumption Pm = (Pe - Po) or net impeller power consumption Pi =

2(e - o) n, where n is the impeller speed [dimension T-1].

Once the desired end-point is determined, it can be reproduced by stopping the

batch at the same level of net power consumption P (for the same mixer,

formulation, speed, batch size and amount/rate of granulating liquid). To account

for changes in any of these variables, you have to compute the Newton power

number Np for the desired end-point:

Np = P / ( n3 d5)

In other words, if you have established an end-point in terms of some Net

Impeller or Motor Power P and would like to reproduce this end-point on the

same mixer at a different speed or wet mass density, calculate Newton Power

Number Np from the given Net Impeller Power P, impeller speed n, blade radius

d, and wet mass density (assuming the same batch size), and then recalculate

the target P with the changed values of speed n or wet mass density .

Wet mass viscosity can be calculated from Net Impeller Power P, blade

radius d and impeller speed n, using the following equations:

P = 2 * n

= * / (n * d3)

where is the net torque required to move wet mass, n is the speed of the

impeller, d is the blade radius or diameter, and is mixer specific viscosity

factor relating torque and dynamic viscosity (note: the correlation coefficient

Page 38 of 48

can be established empirically by mixing a material with a known dynamic

viscosity, e.g. water). Alternatively, you can use impeller torque as a measure

of kinematic viscosity and use it to obtain a non-dimensionless pseudo-

Reynolds number, based on the so-called mix consistency measure, that is,

the end-point torque, as described in the case studies.

Fill Ratio h/d can be calculated from a powder weight, granulating liquid density

(1000 kg/m3 for water), rate of liquid addition, time interval for liquid addition, and

bowl volume Vb. The calculations are performed using the idea that the fill ratio

h/d (wet mass height to blade diameter) is proportional to V/Vb, and wet mass

volume V can be computed as

V = m / ,

where m is the mass (weight) of the wet mass and is the wet mass density.

Now, the weight of the wet mass is computed as the weight of powder plus the

weight of added granulating liquid. The latter, of course, is calculated from the

rate and duration of liquid addition and the liquid density.

Finally, following the examples discussed in the case studies, you can combine

the results obtained at different end-points of the test batch or from different

batches or mixer scales (assuming geometrical similarity).

Given wet mass density , wet mass viscosity , fill ratio h/d ~ m Vb / , setup

speed n, and blade radius or diameter d, you can calculate the Reynolds number

Re (or the pseudo-Reynolds number) and the Froude number Fr. Then you can

estimate the slope a and intercept b of the regression equation

a

Np = b (Re Fr h/d)

or

log Np = log b + a log (Re Fr h/d)

And, inversely, once the regression line is established, you can calculate Newton

Power number Np (which is the target quantity for scale up) and Net Power P

(which can be observed in real time as a true indicator of the target end-point) for

any point on the line.

Page 39 of 48

List of Symbols and Dimensions

a, b Slope and intercept of a regression equation

d Impeller (blade) diameter or radius (m); dimensional units [L]

g Gravitational constant (m / s2); dimensional units [LT-2]

h Height of granulation bed in the bowl (m); dimensional units [L]

H Bowl height (m); dimensional units [L]

l Blade length (m); dimensional units [L]

n Impeller speed (revolutions / s); dimensional units [T-1]

P Power required by the impeller or motor (W = J / s); dimensional units [ML2T-5]

Rb Radius of the bowl (m); dimensional units [L]

q Binder liquid addition rate

s Amount of granulating liquid added per unit time (kg); dimensional units [M]

t Binder addition time (s); dimensional units [T]

Vp Particle volume (m3); dimensional units [L3]

Vm Wet mass volume (m3); dimensional units [L3]

Vb Bowl volume (m3); dimensional units [L3]

w Wet mass; dimensional units [M]

= / Kinematic viscosity (m2 / s); dimensional units [L2T-1]

Dynamic viscosity (Pa*s); dimensional units [M L-1 T-1]

Torque (N-m); dimensional units [M L2 T-2]. End point torque values were

described as wet mass consistency numbers. Note: torque has the same

dimensions as work or energy.

= nd3 / Dimensionless viscosity factor relating net torque and dynamic viscosity

Fr = n2 d / g Froude number. It relates the inertial stress to the gravitational force per unit

area acting on the material. It is a ratio of the centrifugal force to the

gravitational force.

Np = P / ( n3 d5) Newton (power) number. It relates the drag force acting on a unit area of the

impeller and the inertial stress.

Re = d2 n / Reynolds number. It relates the inertial force to the viscous force.

Re = d2 n / Pseudo Reynolds number (m3/s); dimensional units [L-3 T]. Note: this variable

physically is a reciprocal of volume flow rate.

Ga = Re2 / Fr Galileo number

Page 40 of 48

Articles of Related Interest

Electrical Power Systems for Pharmaceutical Equipment; Fluid Bed Processes

for Forming Functional Particles; Fractal Geometry in Pharmaceutical and

Biological Applications A Review; Roller compaction technology for the

pharmaceutical industry; Scale-Up and Postapproval Changes (SUPAC); Tablet

Press Instrumentation.

Literature Reference

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ACKNOWLEDGEMENT

Selected excerpts and figures from M. Levin, Granulation: End-Point Theory,

Instrumentation, and Scale-Up, Education Anytime, CD-ROM Short Course,

AAPS 1999 are reprinted with permission.

Page 48 of 48

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