Granutools

THE FLOWABILITY OF LACTOSE
POWDERS TO OPTIMISETABLETING PROCESSESIn this article, Aurélien Neveu, PhD, Particle Scientist at Granutools; Pauline Janssen,
Product Application Specialist at DFE Pharma; and Geoffroy Lumay, PhD, Associate
Professor at the University of Liege and Co-Founder of Granutools, discuss how newmeasurement methods can help gain a better understanding of the flowability oflactose powders – a necessary step for future improvement of oral delivery systems.
The processability of pharmaceuticalpowder plays a key role in the design
and improvement of production processes
for oral delivery systems (e.g. tableting,capsule filling). To control and optimise
processing methods, material properties
and the behaviour of bulk powder should
be characterised.
Blending is one of the first steps in a
direct compression process and is critical toachieve a homogeneous blend with uniform
API loading. Good flow combined withdensity supports de-agglomeration of an
API during blending (Figure 1).
Free-flowing powder has a relatively
flat powder bed in a blender and tends
to set up a “rolling” motion inside thepowder bed. This results in ball milling of
the API agglomerates, which is beneficial
for the uniform spread of the API particles
over the blend. Poor-flowing powder has ahigher dynamic angle of repose and tends
to avalanche. This results in less motion
inside the powder bed and less ball millingof agglomerates. De-agglomeration of the
API is beneficial to achieve good content
uniformity in a pharmaceutical formulation,and this becomes more critical with alower API dose.
Moreover, good flowing properties of apowder are also required for flow through58

the tableting system, resulting in uniform
flow into the die cavities. Insufficient
flow can lead to uneven filling of thedies, resulting in large weight and dosage
variations of the final tablets. At hightableting speeds, the time to fill dies isreduced, making flow properties of theblend even more important. The particle
properties, mainly size and shape, strongly
influence the flowability of the powder
and thus the critical filling velocity
achievable in die filling.1

Pauline Janssen
Product Application Specialist
T: +31 6 2115 4579
E: pauline.janssen@dfepharma.com
DFE Pharma
Kleverstrasse 187
PO Box 20 21 2047568 Goch
Germany
www.dfepharma.com

Dr Aurélien Neveu
Particle Scientist
T: +32 470 18 60 18
E: aurelien.neveu@granutools.com

Dr Geoffroy Lumay
Associate Professor and
Co-Founder of GranuTools
T: +32 43 66 44 21
E: geoffroy.lumay@uliege.be

Granutools
Rue Jean-Lambert Defrêne 107
4340 Awans
Belgium

University of Liège
Place du 20 Août 74000 Liège
Belgiumwww.granutools.com

www.uliege.be

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Granutools

Mass flow rate (F in g/s) was investigatedfor different hole size D (from 2–28 mm).
The Beverloo parameter (Cb in g/mm3) andthe minimum aperture size to obtain a flow
Dmin are deduced from the regression with
Beverloo law:
F = Cb √g (D – Dmin)2,5

Figure 1: Free-flowing powders tend to set up a rolling motion inside the powder
bed, resulting in ball milling of the API agglomerates. Poor-flowing powder tends toavalanche and results in less motion inside the powder bed and less ball milling of
API agglomerates.

“Good flow of apharmaceutical formulationis critical to produce
uniform dosage forms.”

results are then compared and extended toa vertical flow through an aperture, in ageometry closer to those encountered in die
filling. Then, the effect of the process speed
on the flowability – i.e. the rheologicalbehaviour – is investigated with the rotating
drum measurement method.

EXPERIMENTAL METHOD
Consistent flow is also important forcontinuous manufacturing processes, which
are gaining more and more interest fromthe pharmaceutical industry. Raw material
feeding is usually one of the first units ofoperation in a continuous manufacturingline. The ability to feed powder consistently
and continuously is regarded as one of thecritical requirements for finished productquality and therefore stringent control on
feeding is required.
Lactose is one of the most widely used
excipients in the pharmaceutical industry.
There are many reasons for its popularity,
the fact that lactose is largely inert,
relatively inexpensive, safe, many different
grades are available and it has a long
history of usage in successful formulations
worldwide. For direct compression processes
such as tableting, lactose excipients canbe used as a filler-binder to provide bulk
density, compaction and flow to theformulation. Good flow of a pharmaceuticalformulation is critical to produce
uniform dosage forms.
In this article, we present how newmeasurement methods can help to gain abetter understanding of the flowability oflactose powders, which is a necessary stepfor future improvement of oral delivery
systems. Firstly, the well-known angle ofrepose is estimated to get a first screeningof the cohesiveness of the powders. These
Copyright © 2020 Frederick Furness Publishing Ltd

Repose Angle (GranuHeap)
The GranuHeap instrument is an
automated heap shape measurement
method based on image processing andanalysis. To create the powder heap, an
initialisation tube with an internal diameter
equal to that of the circular support (40mm) is filled with 100 mL of powder.
The tube then moves upward at a constant
speed of 5 mm/s, allowing the powder toform a heap on the cylindrical support
in a repeatable way. In the present
study, 16 pictures of the heap, separated
by a rotation of 11.25°, are taken andanalysed by a custom image recognition
algorithm to determine the position of
the powder/air interface and compute therepose angle.
Flow through an aperture (GranuFlow)
The GranuFlow instrument is a laboratory
hopper allowing the aperture size to beeasily modified with a rotating device.
The flow rate as a function of the aperturesizes D is measured with an electronicbalance connected to a computer toobtain a complete flow curve. This flow
curve is fitted with a theoretical model toextract the main parameters: the minimum
aperture size (Dmin) and the Beverloo
parameter (Cb) related to the flowabilityof the sample.

Dynamic Cohesive Index (GranuDrum)The rheology of powders is investigatedwith the GranuDrum, an automatedpowder flowability measurement method
based on the rotating drum principle.
A small amount of powder (50 mL in thisstudy) is placed in a horizontal drum withtransparent sidewalls. The drum rotatesaround its axis at an angular velocity ranging
from 2–60 rpm. Snapshots (40 images
separated by 1s) are taken by a chargecoupled device (CCD) camera for eachangular velocity. The air/powder interface
is detected on each picture with an edge
detection algorithm. Afterwards, the averageinterface position and the fluctuations
around this average position are computed.
For each rotation rate, the dynamic
cohesive index is measured from theinterface fluctuations, which are solely due
to the cohesive forces acting between thegrains. The dynamic cohesive index is thus
close to zero for non-cohesive powders andincreases when the cohesive forces intensify.
Furthermore, by varying the rotation rate,complex rheological properties of powders(shear thinning, shear thickening andthixotropic behaviour) can be investigated.

MATERIALS
Five lactose powders provided by DFE
Pharma have been selected for this study,
mainly differing in their production methods:•	Pharmatose® 450M: a fine-milled alphalactose monohydrate•	SuperTab® 24AN: a granulated anhydrous
lactose•	SuperTab® 30GR: a granulated lactose•	SuperTab® 21AN: an anhydrous lactose•	SuperTab® 11SD (EU): a spray-driedlactose.
Pharmatose® 450M is a milled lactose
grade which is commonly used in wet anddry granulation processes. SuperTab® grades
are high-end lactose grades specificallydesigned for direct compression processes
and provide additional functionality interms of flow and compression.

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59Granutools

SuperTab® 21AN

SuperTab® 24AN

SuperTab® 11SD

SuperTab® 30GR

Pharmatose® 45OM

Table 1: SEM images of the particles making up the powders.

SuperTab® 21AN

SuperTab® 24AN

SuperTab® 11SD

SuperTab® 30GR

Pharmatose® 45OM

Type

Anhydrous

Anhydrous granulated

Spray dried

Granulated

Milledx10 (µm)

24

40

44

38

3

x50 (µm)

180

121

119

126

18

x90 (µm)

387

298

223

297

49

Table 2: Type and size distribution of the particles making up the five powders.
Table 1 provides scanning electron
microscope (SEM) images of the powder’sparticles, revealing the shapes of the grains.
Particle size distributions are summarisedin Table 2.

RESULTS AND DISCUSSION
Repose Angle
Figure 2 presents the measured angle ofrepose for all powders. It appears that
the Pharmatose® 450M and SuperTab®
21AN exhibit a similar angle of repose,
higher than the other ones. Powders canthen be classified in two categories with athreshold angle of repose around 55°, above
which they are expected to have higher
bridging propensity. Moreover, based on its
lower angle of repose, the SuperTab® 11SD
is expected to have the lowest bridging
propensity, closely followed by SuperTab®
30GR and SuperTab® 24AN.
Pharmatose® 450M has the lowest particle
size and thus it is not surprising it exhibits ahigher cohesiveness and thus a higher angleof repose.2 However, particle size is not the
only parameter affecting flow, as it also
depends heavily on powder morphology,
as can be observed for SuperTab® 11SD
which has a spherical shape.
Vertical flow
Figure 3 presents the mass flow rate versus
the silo aperture for the three powders
able to flow through the maximum tested
aperture size (28 mm). First of all, only
the SuperTab® 24AN, SuperTab® 30GR
60

Figure 2: Mass flow-rate versus aperture for the three powders able to flow throughthe larger aperture (28mm).

“The cohesiveness of apowder depends on thesize of the particles thatmake up the powder: thesmaller the particle, thehigher the cohesion.”and SuperTab® 11SD were able to flow
through the larger aperture size (28 mm)
tested in this study, in coherence withthe lower repose angle measured with
the GranuHeap.

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The SuperTab® 11SD has the highest
Beverloo parameter and thus exhibits thebest flowability through the silo aperture.
This powder has also the lowest Dmin andis thus able to flow though a smaller aperturethan the other ones. It is then followed
by SuperTab® 30GR and SuperTab®
24AN, in this order, in total accordancewith the angle of repose measurements
obtained with the GranuHeap.
The cohesiveness of a powder depends
on the size of the particles that make up thepowder: the smaller the particle, the higher
the cohesion. However, other characteristicsof the grains can play a role – such as theshape, the surface roughness or the chemical
properties. For the powders we considered,
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Granutools

Figure 3: Mass flow rate versus aperture for powders.
it appears that the SuperTab® 21AN has thehigher median particle size (x50=180 µm)
but also a high bridging propensity, as it was
not able to flow through the 28 mm aperture.
Considering the three powders that did
flow through the 28 mm aperture (SuperTab®
11SD, SuperTab® 30GR, SuperTab® 24AN),
the SuperTab® 11SD has the lowest particle
size but also the lowest Dmin and highest
Cb. Therefore, the shape of the particles
seems to be a more relevant characteristic toexplain the flowability performance of these
powders. Indeed, although the SuperTab®
11SD particles are smaller, they have aregular spherical shape which promotes
the flow. The SuperTab® 30GR and theSuperTab® 24AN are granulated powders
composed of agglomerates of slightly roundshapes, explaining why they also exhibit agood flowability.
The more irregular shape of particlesof the SuperTab® 21AN leads to increased
bridging propensity due to interlocking
effects. Pharmatose® 450M combines
irregular particle shapes with the smallest
particle size (x50=18 µm) – this powder isthus expected to have the lowest flowability.
The obtained results indicate the sameranking of hopper diameters for theselactose grades as shear cell measurements
did before (SuperTab® 24AN was notconsidered in this experiment). With theprevious shear cell measurements, theminimal required hopper dimensions in a
conical hopper were predicted. Hopper outlet
diameters were predicted to be the lowest
for SuperTab® 11SD (15 mm), followed bySuperTab® 30GR (17 mm). SuperTab® 21AN
was predicted to require a higher minimum
hopper outlet of 96 mm, due to its relatively
Copyright © 2020 Frederick Furness Publishing Ltd

high wall friction. For Pharmatose® 450M,
the predicted hopper diameter was 210 mm.3
Dynamic cohesive index
Cohesive index values as a function of
the increasing rotating speed are presented
in Figure 4. The observations and theclassification obtained with GranuHeap
and GranuFlow are consistent with theGranuDrum for equivalent stress state,i.e. at low rotating speeds. Moreover,the cohesive index gives another level ofdescription as it allows us to distinguish
the SuperTab® 21AN and the Pharmatose®
450M. It is evident that the Pharmatose®
450M exhibits the most cohesive behaviour,with a cohesive index much higher for thewhole speed range. This is consistent withthe significantly lower particle size of thispowder (x50=18 µm).
Pharmatose® 450M, SuperTab® 11SD,
SuperTab® 24AN and SuperTab® 30GR
show shear-thickening behaviour, meaningthat their cohesiveness increases with process
speed. This decrease of flowability may
limit the critical filling velocity achievablein oral delivery production processes.
On the contrary, SuperTab® 21AN shows
strong shear-thinning behaviour, leading toa cohesive index at high speed equivalent
to those of the best flowing powders at low
speed. Therefore, this powder is expected
to perform the best at higher processing
speeds. The larger particle size and irregular“The proper characterisation of powder flowability is a
key step in understanding and improving manufacturing
processes of oral delivery systems.”

Figure 4: Cohesive index versus rotating drum speed. Shear-thickening
behaviours are observed, except for powder SuperTab® 21AN, which exhibits strong
shear-thinning behaviour.
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Granutools

particle shapes may explain why this powder
differs strongly from the others.

CONCLUSIONSThe proper characterisation of powder
flowability is a key step in understanding
and improving manufacturing processes oforal delivery systems. For this reason, theflowability of five lactose powder grades
was investigated. The SuperTab® 11SD,

SuperTab® 24AN and SuperTab® 30GR
showed the best flowability with GranuHeap,
GranuFlow and GranuDrum instruments.
It appeared that SuperTab® 21AN did
not exhibit the best flowability despite
the large particle size of this lactose
grade, explained by the irregular shapeof the grains. The small particle size of
Pharmatose® 450M led to a much higher
cohesiveness and poor flowability comparedwith the other studied powders. Moreover,

ABOUT THE AUTHORS
Aurelien Neveu’s research activities mainly focus on the understanding of granularmaterials at different scales. During his PhD he developed discrete numerical models to
describe fragmentation mechanics of cohesive granular materials by taking into accountthe complex micro-properties of the grains. Dr Neveu then moved to study segregationin gravity-driven rapid flows as well as aeolian transport of granular materials, with huge
implications for natural disasters. He is now working as a particle scientist at Granutools,
performing research on powder characterisation.
Pauline Janssen is a Product Application Specialist in oral solid dosage (OSD) at DFE
Pharma. She has been working on application development of excipients based on
fundamental knowledge of excipients and powder physics. Ms Janssen joined DFE
Pharma at the beginning of 2017 and worked as a product developer on multiple OSD
and DPI projects. As an analytical expert, she supported the design of experiments tounderstand products and their usage.
Geoffroy Lumay is Associate Professor and Soft Matter Physics Chair at the University ofLiege in Belgium. Dr Lumay is leading research projects in the field of soft matter physics
at the intersection between fundamental sciences and industrial applications. He teaches
both basic and advanced physics to students in pharmaceutical sciences, engineeringand agronomy. Dr Lumay co-founded the company Granutools, which is developing,producing and commercialising a range of laboratory instruments dedicated to powder
characterisation.

shear thickening is observed except for theSuperTab® 21AN which showed strong
shear-thinning behaviour.
For inherently dynamic processes,
especially in continuous manufacturing lines,
this improved knowledge of rheologicalbehaviour
providesindispensable
information to develop and select the mostsuitable powder.

ABOUT THE COMPANY
Granutools
combines
decadesofexperience in scientific instrumentation
with fundamental research on powder
characterisation,todevelopandmanufacture instruments that measurephysical powder characteristics such as
flow, static cohesion, dynamic cohesion,
tapped density and tribo-electric charge.

REFERENCES
1.	Zakhvatayevaa A, Zhonga W,
Makrooa HA, Harea C, Wu CY,“An experimental study of die fillingof pharmaceutical powders using
a rotary die filling system”. Int J
Pharm, 2018, Vol 553, pp 84–96.
2.	Boschini F, Delaval V, Traina K,
Vandewalle N, Lumay G, “Linking
flowability and granulometry of
lactose powders”. Int J Pharm,
2015, Vol 494, pp 312–320.
3.	“Understanding the differences
between lactose grades in termsof powder flow”. Technical Paper,
DFE Pharma.

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