Chemical Engineering Journal 328 (2017) 785–815

Contents lists available at ScienceDirect

Chemical Engineering Journal

journal homepage: www.elsevier.com/locate/cej

Review

A comprehensive review on process and engineering aspects of

pharmaceutical wet granulation
P. Suresh a, I. Sreedhar a,⇑, R. Vaidhiswaran a, A. Venugopal b
a
Department of Chemical Engineering, BITS Pilani Hyderabad Campus, Shameerpet (Mandal), Hyderabad 500078, India
b
I & PC Division, IICT, Tarnaka, Hyderabad, India

h i g h l i g h t s g r a p h i c a l a b s t r a c t

Granulators and their design.

Granule attributes and their
characterization.

Process control and optimization.

Modelling and simulation.

Kinetics and scale up.

a r t i c l e i n f o a b s t r a c t

Article history: Wet granulation is a very important unit operation that finds applications in many industries mainly
Received 21 April 2017 pharmaceutical and chemical industries. Various granulation technologies in batch and continuous
Received in revised form 13 July 2017 modes were employed viz., high shear granulators, fluid bed granulators, twin screw granulators and
Accepted 14 July 2017
the novel ones like foam granulators, steam granulators, dry granulators etc. In this review, various
Available online 16 July 2017
aspects of pharmaceutical granulation like technologies, characterization tools, process control, mod-
elling and simulation, kinetics and scale up have been thoroughly analysed and discussed in terms of
Keywords:
development trends and future challenges and prospects. The critical role played by various off line
Wet granulation
Granulator design
and inline characterization tools was highlighted along with their applications. Studies from PBM,
Modelling and simulation DEM to hybrid models, CFD and ANN based models were presented in terms of their performance and
Granule attributes and characterization challenges. Kinetic studies to understand the rate and influencing parameters of various steps involved
Process control in granulation process with controlling regimes were discussed along with the models used. The scale-
Kinetics up, a major challenge in granulation was also discussed in terms of the methodology and efficiency in
Scale-up retaining the granule attributes with proper control of process parameters was also presented. Process
control protocols employed in the wet granulation process was discussed along with the relations of

Abbreviations: AE, Acoustic Emission; ANN, Artificial Neural Networks; API, Active Pharmaceutical Ingredient; BET, Brunauer–Emmett–Teller; CFD, Computational Fluid
Dynamics; CIP, Constrained Interpolation Profile; CQA, Critical Quality Attributes; DEM, Discrete Element Model; ECT, Electrical Capacitance Tomography; EKE, Equipartition
of Kinetic Energy; ETM, Equipartition of Translational Momentum; FBG, Fluid Bed Granulators; FBMG, Fluidized Bed Melt Granulation; FBRM, Focused Beam Reflectance
Measurement; FDA, Food and Drug Administration; FG, Foam Granulation; GP, Granule Porosity; GSD, Granule Size Distribution; HPMC, Hydroxy Propyl Methyl Cellulose;
HSWG, High Shear Wet Granulators; KF, Karl Fisher; LDV, Laser Doppler Velocimetry; LOD, Loss On Drying; LSWG, Low Shear Wet Granulators; MCC, Micro-Crystalline
Cellulose; MPC, Model Predictive Control; MRI, Magnetic Resonance Imaging; MTR, Mixer Torque Rheometry; NIR, Near Infra-Red; PAT, Process Analytical Technologies; PBA,
Pendulum Bridge Apparatus; PBM, Population Balance Model; PDPA, Phase Doppler Particle Analyser; PEPT, Positron Emission Particle tracking; PFR, Powder Feed Rate;
PMMA, Poly Methyl MethAcrylate; PSD, Particle size diameter; PTFE, Poly Tetra Fluoro Ethylene; QbD, Quality by Design; ROM, Reduced Order Models; RPWG, Reverse Phase
Wet Granulation; RTD, Residence Time Distribution; SCG, Super Critical Granulators; SEM, Scanning Electron Microscopy; SFV, Spatial Filter Velocimetry; SG, Steam
Granulation; SI, Size Independent; SS, Stainless Steel; SSA, Specific Surface Area; TGA, Thermal Gravimetric Analysis; TSG, Twin Screw Granulators; XRPD, X-Ray Powder
Diffraction.
⇑ Corresponding author.
E-mail address: isreedhar2001@yahoo.co.in (I. Sreedhar).

http://dx.doi.org/10.1016/j.cej.2017.07.091
1385-8947/Ó 2017 Elsevier B.V. All rights reserved.
786 P. Suresh et al. / Chemical Engineering Journal 328 (2017) 785–815

different granule and tablet attributes to process and design parameters. The future challenges and pro-
spects in the above mentioned aspects were listed for prospective researchers.
Ó 2017 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 787
2. Mechanism of granulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 787
3. Wet granulation technologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 788
3.1. Classification of technologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 788
3.2. Types of wet granulators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 788
3.2.1. Mechanical granulators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 788
3.2.2. Fluid bed granulator . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 790
3.2.3. Spray drying granulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 790
3.2.4. Twin screw granulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 791
4. Novel granulation techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 791
5. Characterization tools for various granule attributes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 793
5.1. Offline/end product characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 793
5.2. In-line characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 794
6. Modelling and simulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 794
6.1. Summary of modelling and simulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 798
7. Kinetics studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 801
7.1. Summary of kinetic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 802
8. Scale up studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 802
8.1. Summary of Scale-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 804
9. Process control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 805
10. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 807
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 807
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 807

Nomenclature

e Porosity ~
w Rotational velocity vector at current time step
W Weight of liquid Length of the time step
!s
D
ql Density of liquid v n Normal collision velocity
!
qs Density of the solid v t Tangential velocity
h Convective heat transfer coefficient of the particle K Spring constant
kp Conductive heat transfer coefficient of the particle g Damping coefficient
dp Diameter of the particle l Coefficient of friction
k Latent heat of vaporization n Tangential overlap
!
Lht Entry length Ft Tangential forces
Tg Inlet gas temperature !
Fn Normal forces
Tl Liquid temperature
F(x,t) F is the density of each particle and x is the vector
A Area of bed
Rform Birth rate of the particles having internal properties x
mo Evaporation rate of liquid
Rdepletion Death rate of the particles having internal properties x
wa Spray flux
F(s,l,g,t) s, l, g are vectors which represent the solid, liquid, and
Vo Volumetric spray rate
Gas volumes in a granule
Ao Spray area
Raggregation Net rate of aggregation
dd Average droplet diameter
Rbreak Net rate of breakage
sp Drop penetration time
Rnucleation Net rate of nucleation
tp Time taken for a drop to fully penetrate the powder bed
Xin Molar concentration of the in-flow properties
tc Time taken for the exposed surface of powder to circu-
Xout Molar properties of the out-flow properties
late back to the spray zone
~ Stdef Stokes Deformation number
G Gravitational acceleration
Uc Representative collision velocity of Granules
Fp Sum of the forces on the particle caused due to other
Pd Tapped density after vibration
particles
Ad Bulk density untapped
Fw Sum of the forces on the particle caused by walls
qEV Envelope density
I Inertia
~ qs Skeletal density
R Position vector at current time
~ qbd Maximum compressed density
V Velocity vector at the current time step
SSA Specific Surface area
 P. Suresh et al. / Chemical Engineering Journal 328 (2017) 785–815
RVS Relative volume to surface area ratio
N0 Avogadro’s Number
ACS Cross sectional area of adsorbate
M Mass of the sample
TGA Thermal gravimetric analysis
n Scaling Index
N Impeller Speed
D Impeller diameter
1. Introduction
Granulation involves agglomeration of fine particles into larger
particles called granules, with controlled properties viz., strength,
porosity, flow, compressibility, bulk density and particle size distri-
bution (PSD-0.1–2 mm) distinguishable from the original fine par-
ticles [1,2]. Also, it enables easier material handling and to control
the disintegration and dissolution characteristics, bulk density and
API content uniformity of tablets, the end product in pharmaceuti-
cal industry [3–6]. In the chemical industry, nearly 60% products
were produced in granular form [7]. It is even more important in
the pharmaceutical applications as it enables better control of drug
content uniformity at low drug concentrations besides achieving
desired product bulk density and compactibility even for high drug
levels by improving powder functionality through micronized APIs.
Granulation process could be classified as wet and dry types
depending on whether or not a liquid binder was used in the pro-
cess. In conventional wet granulation, a liquid solution was added
to an agitated powder blend to form wet mass of desired PSD,
which was then dried and processed [8]. The granules were held
together by adhesive forces between the binder and the solid sur-
face besides the capillary and viscous action of the liquid solution
[9,10]. Wet granulation was predominantly used in the pharma-
ceutical industry to manufacture tablets, the most accepted form
of drug delivery [11] and also to manufacture granules of varying
density. Moreover, the use of such a liquid binder results in
enhanced compaction characteristics [12]. Sun et al., [13] have
studied the optimal level of binder/lubricant-water combination
on microcrystalline cellulose to enhance flow properties and tablet
compaction. It also ensures improved homogeneity of granules
(API and excipients) and close contact between excipients such
as pH modifiers, stabilizing agents and the API [14]. But wet gran-
ulation was expensive in terms of equipment cost and efficient
process control needed besides the undesirable effects of moisture
content in APIs and then tablets, if not controlled effectively
[15,16]. Nevertheless, wet granulation till date is still very popular
in the pharmaceutical industry. In contrast, dry granulation was
relatively a simple and cost effective process consisting of com-
paction and milling steps significantly increasing the bulk density
of voluminous drugs. It was best suited for moisture and heat sen-
sitive drugs as it was free from organic solvents or binders. But it
produced dusts or fines with impaired compaction attributes of
the granules [17]. Many studies were reported on wet granulation
which was more than fifty years old in terms of granulator design,
process control, characterization tools to assess granule attributes,
modelling and simulation, scale up and kinetics [18,19].
In this paper, wet granulation mostly focussing on pharmaceu-
tical applications was critically and comprehensively reviewed in
terms of granulation mechanism and technologies, granule attri-
butes and their in-line and off-line characterization tools, process
control, modelling and simulation, scale up and kinetic studies.
Challenges and future prospects on each aspect were also
highlighted.
787
Fr Froude Number
w binder to solid ratio
AR Aspect Ratio of the primary particles
S Liquid pore saturation
c Liquid surface tension
Y Yield stress
Df Fractal dimension for coalescence
2. Mechanism of granulation
The wet granulation process comprises two main periods of
binder introduction where a liquid binder was sprayed or poured
or dripped into powder mix to form sticky surfaces which coalesce
during mutual collisions and wet massing during which consolida-
tion and growth happens due to the relative movement of different
particles in the mixer and presence of sticky surfaces. Unless car-
ried out in different vessels, these two processes were always inte-
grated and cannot be separated either spatially or temporally,
making the process complicated in terms of process control, kinet-
ics and scale-up [20]. Wet granulation has three rate processes viz.,
wetting and nucleation, where the liquid binder was brought in
contact with a dry powder bed and is distributed through the
bed to form nuclei granules; consolidation and growth, where col-
lisions between two granules, granules and feed powder, or a gran-
ule and the equipment lead to granule compaction and growth;
and attrition and breakage, where wet or dried granules break
due to impact, wear or compaction in the granulator or during sub-
sequent product handling. These rate processes would determine
the granule attributes which in turn were dependent on the formu-
lation (powder, binder) and process factors (granulator and operat-
ing parameters) [21,22]. These rate processes along with their
controlling parameters were shown in Fig. 1 below.
Wetting represents introduction of liquid binder into the dry
powder and its distribution throughout the bed to form liquid
bridges between the particles while nucleation is the process in
which the initial nuclei of granules were formed. It has been
reported that wetting and nucleation and thereby granule attri-
butes were influenced by parameters like nature and amount of
liquid binder and its properties like viscosity, density, wettability,
solid-liquid contact angle, liquid droplet size. While viscosity, nat-
ure and amount of binder, spray rate and droplet size determine
the controlling step in the granulation mechanism and thereby
the kinetics; surface tension and contact angle were found to affect
the power requirement [23–25]. In melt granulation, it was found
that fine powders of binder gave lower agglomerate growth rates,
while coarse or flakes of binders showed similar growth rates at
moderate viscosities and an increased growth rate at higher vis-
cosities [26]. A similar study established that there exists a critical
upper limit on the binder viscosity (around 1000 mPa s), beyond
which very high impeller speeds were required thereby large
power to counteract uncontrollable growth rate [27]. Granule
growth was also seen to be strongly influenced by the extent of
pore saturation with binder which in turn was dependent on pro-
cess conditions and formulation conditions. Capes et al., [19] estab-
lished the equation for weight of saturation for the liquid as
eql
W¼ ð1Þ
ð1  eÞqs þ eql
(where e = porosity of the particle, ql = Density of Liquid and
qs = Density of Solid.)
788 P. Suresh et al. / Chemical Engineering Journal 328 (2017) 785–815
Fig. 1. Stages of wet granulation with influencing parameters.
Coalescence and consolidation step represents the growth and
densification of granules due to collisions. This process influences
porosity of the granules that has a direct bearing on end proper-
ties like strength, hardness and dissolution characteristics. Some
of the other parameters that influence this process are nature of
binder, mode of addition (spraying or pouring) and viscosity of
the binder. It has been reported that increase in viscosity had
negative effect on the rate of consolidation [24,28,29]. Vialatte
et al., [30] observed positive influence of spray rate on granule
size and bulk density. It was found that granules undergo three
growth regimes and transition between them would depend on
the physico-chemical properties of solids and binder, operating
conditions and experimental procedure adopted. The impeller
speed was also found to have a direct impact on granule growth
with higher speeds resulting in the formation of denser granules.
The attrition and breakage step represents the breakage of gran-
ules due to impact, wear and compaction in the granulator. This
process represents the interplay between various dynamic forces
in the granulator having a strong influence on the final PSD of
granules, granule homogeneity and strength [31,32]. Stronger
dynamic forces were reported to lead continuous rupture fol-
lowed by immediate coalescence [33,34].
The efficiency of wet granulation was found to be dependent
on proper control of adhesive and cohesive forces between the
particles that were in turn affected by the nature and quantity
of wetting fluid, binder used and mixing time. Studies by Soyeuxa
et al., [6] showed that there was an optimum concentration of
binder to achieve the best hardness to disintegration ratio beyond
which it resulted in increasing hardness of the granules. This crit-
ical binder to powder ratio could be determined by careful char-
acterization of the binder-liquid particle interaction employing
tools like Mixer Torque Rheometry (MTR) [35,36]. MTR allows
us to measure the torque/power consumption as a function of
the amount of binder added and a sharp change in the depen-
dency signifies the presence of critical amount of binder required
[37,38]. This technique has also been used in scale up studies to
understand the process at a micro level for successful scale-up
[39]. Other tools such as Pendular Bridge Apparatus (PBA) could
also be used to test the binder interaction with particle or specif-
ically in identifying the binder strengthening rates [23,40] besides
estimating the relative binding strength as a function of force
exerted and critical rupture time. These tools help in making
the right choice of the nature and amount of binder by assessing
its properties [41].
3. Wet granulation technologies
3.1. Classification of technologies
Wet Granulation could be carried out in three modes viz, batch,
semi-batch and continuous. The common types of granulators viz.,
fluid bed and mechanical granulators could be operated in both
batch and continuous modes. Mechanical granulators in batch
mode were low or high shear type and those in continuous mode
were mixers or extruders. Spray type granulation is a continuous
operation. It was found that continuous mode was preferred to
the batch mode in terms of improved quality by effective process
control, reduced processing times and operating costs. Further-
more, studies by Schaber et al., [42] had also shown that continu-
ous processing was economically more viable than batch
processing. Continuous processing however limits the application
of conventional off-line testing and demands the use of sophisti-
cated and expensive in-line and real time characterization tech-
niques for effective process control.
3.2. Types of wet granulators
3.2.1. Mechanical granulators
Mechanical granulators work based on the mechanical forces
such as shear. Based on the amount of shear provided on the gran-
ulation mix by the impeller blades, they could be classified as low
shear wet granulators (LSWG) (typically < 150 rpm) and high shear
wet granulators (HSWG > 200 rpm). These granulators were typi-
cally employed in batch mode.
LSWG work on lower agitator speeds, have lower sweep vol-
umes and lower pressures on the powder bed than high-shear mix-
ers or fluid bed granulators (FBG) [43]. Though limited in use, they
were extensively employed for shear sensitive materials [44]. The
agitator could also be used to add binding liquid to the powder
mix. These intensified granulators could allow mixing, granulating
and drying in the same equipment. Some commonly used low-
shear wet granulators were ribbon and paddle blenders, planetary
mixer granulators, orbiting screw granulators, sigma-blade granu-
lators and rotating-shape mixer/granulators.
In a HSWG, an impeller rotating at very high speeds keeps the
powder in agitation in a closed vessel with binder solution sprayed
from the top. First nuclei of granules were formed by dispersing
the liquid-binder droplets into the powder. Development of large
agglomerates was prevented by the agitation forces as they would
 P. Suresh et al. / Chemical Engineering Journal 328 (2017) 785–815
be too fragile to sustain the shear. With continued mixing and
spraying, densification of these agglomerates occurs by the squeez-
ing out of the internal binder. This would make agglomerates not
only harder but more adhesive promoting the growth of granules.
The process was stopped at a certain point called phase inversion
that results due to excessive densification beyond which there
would be uncontrolled growth of granules. This was then followed
by drying either in separate equipment or in the same by single pot
method. It was one of the most popular methods of granulation in
the pharmaceutical industry because of its ability to produce high
drug loading leading to small dosage [45], lower amount of liquid
binder, better drug distribution in the final product, improved dis-
solution properties of the tablet and short processing times. It
however had some disadvantages like mechanical degradation of
fragile particles, chemical degradation of thermally sensitive mate-
rials at high temperatures and possible lump formation due to over
wetting [46–48].
The shape, size and speed of impeller or chopper and geometry of
the granulator bowl, fill ratio, bowl material were critical parame-
ters that have a major impact on physical and mechanical properties
of the granules in these granulators [43,46]. The dynamics of pow-
der mixing and flow patterns change with the shape of the granula-
tor bowl and impeller. This influences the extent of sweep volume
which in turn affects the degree of densification of granules
[49,50]. Shaefer et al., [51] demonstrated that the difference in gran-
ule growth for dicalcium phosphate and lactose in horizontal and
vertical granulators with higher liquid saturation levels required
in vertical configuration due to stronger mechanical forces [43].
The effect of fill ratios has been investigated by Bock and Kraas
et al., [52] who observed that higher fill ratios in the bowl result in
greater amounts of fines being formed. Overloading could also lead
to inadequate mixing and granulation [53]. Generally, a fill level of
50%–70% of the total bowl size was used. The mechanical energy
supplied to the powder bed was dissipated if under-loaded which
would eventually lead to poor granulation. A study by Bouwman
et al., [54] showed the effect of material of construction of granu-
lator viz., SS, glass, PMMA and PTFE on final granule properties
using various excipients. It was found that granules made in glass
and stainless steel vessels were very distinct from those made in
PMMA and PTFE vessels in terms of size. The contact angle of the
material and the wetting rate of the powder employed were found
to play a critical role on the granule size distribution (GSD). Glass
and SS had low contact angle, thereby leading to improper liquid
distribution on the powder bed and hence broader GSD. The effect
of impeller and chopper design on the granule growth of dicalcium
phosphate has been investigated by Holm [55]. The study was con-
ducted using three different impeller blades (with different angles
of inclination) having the same surface area. It was found that at
high impeller speeds, impeller blades with high inclination pro-
duced granules having low porosity, narrow PSD resulting in sig-
nificant consolidation and compaction of the granules [56]. It has
also been found that granules of low porosity and high strength
were obtained when high impeller speeds were used [23,29,46].
Impeller design also has an impact on downstream aspects like
material handling and transportation besides some end use prop-
erties such as survival during handling, compaction and dissolu-
tion rates [57]. Studies by Borner et al., [48] showed that a two-
bladed impeller was more robust than a three bladed design and
hence was more suitable for pharmaceutical applications giving
desired flow patterns and higher dilation of particle bed [58]. The
shear effects of the impeller on the properties of granules prepared
were investigated by Oulahna et al., [46] Kwan et al., [59] Mack-
aplow et al., [60] and Bock and Kraas et al., [52]. The effect of
impeller speed on the granule properties other than PSD has been
reported by Ohno et al., [61] and Gabbott et al., [62]. In these stud-
ies, mechanical energy imparted by the impeller was found to have
789
an impact on the physico-chemical characteristics of the powder-
binder agglomerate, which in turn affects the final granule proper-
ties. Hoornaert et al., [63] reported that in a HSWG, appropriate
chopper design would lead to the formation of fine granules of
uniform GSD. Oka et al., [64] studied the effect of wet massing
time, L/S ratio and impeller speed on GSD, porosity and morphol-
ogy of the granules. The study showed that while L/S ratio had pos-
itive effect on the mean granule size, it had negative effect on
porosity. On the other hand, wet massing time was found to have
negative influence on porosity and tablet strength with marginal
influence on tablet density due to increased compaction forces
and irreversible deformation of granules caused during long wet
massing times [65]. The binder viscosity too significantly affects
the granule properties where for a binder of high viscosity, granule
size increased and strength decreased with impeller speed and vice
versa for a low viscous binder [66]. The initial moisture content
was found to have a positive influence on the coalescence process
due to an increased saturation that also led to increased porosity,
increased flowability due to increased granule size and blend den-
sity but poor tabletability [14,67]. Also solid volume in the granule
(as a result of increasing porosity) decreased with increase in the
moisture content according to the power law. The exponent for
this relationship was the fractal dimension (Df) associated with
the coalescence, which was independent of the population fraction
considered and the binder used [68–71]. Hence controlling initial
moisture content was very vital in achieving robust manufacturing
process as per QbD (quality by design) as it has contradicting
effects. Also an increase in the granulation time was found to form
denser granules but with low porosity and tablet friability.
Since the granulation process was predominantly used in
pharma industry, it is important to understand various tableting
properties like hardness, density, tabletability, dissolution rate
etc. It is preferred to have high hardness and fast in vitro dissolu-
tion. Studies by Gabbott et al., [72] suggested that high energy
granulation processes; i.e. long granulation time, high impeller
speed and high water quantity, formed dense granules probably
due to over granulation and hence slower release of drugs from
tablets. Several studies have been reported on the effect of degree
of over-granulation and the influencing parameters to determine
the exact end-point for granulation [73–76]. Mechanistic under-
standing of over granulation problem was very vital for the devel-
opment of robust and efficient formulation and HSWG process. It
was found that over granulation was caused with water levels
between 65% and 70% leading to larger granules with poor
tabletability. Hence size reduction could be a way to address over
granulation besides using effective in-situ and online monitoring
controls of the end-point. Yeboah et al., [77] studied the effect of
formulation on over-granulation and suggested few excipients to
overcome this problem. Experimental results also demonstrated
that varying the geometry of the equipment requires technical set-
tings to vary accordingly, in order to have identical physical char-
acteristics of the end product [46]. Recent studies were focused on
the impact of input ingredients (feed and binder) along with their
hydrophobicity on granulation performance and final granule
properties like size, structure, strength, density [78–84]. In the
pharmaceutical applications, even the API content was found to
have a bearing on the granule attributes. When it was low, excip-
ients played a major role on granule properties, while its own
properties were responsible when used in large content [20,85].
Thus, generalization of parameters for a given end product prop-
erty could not be made, without considering the APIs and their
composition in the formulation.
It could be summarized that the high shear wet granulation
process was influenced by various parameters like feed size and
properties, impeller design and speed, nature, amount and rate of
binder employed which in turn influence the granule attributes
790 P. Suresh et al. / Chemical Engineering Journal 328 (2017) 785–815
like GSD and strength. Due to the agitation by the impeller, the bin-
der gets uniformly distributed on the powder surfaces causing
nucleation, consolidation and growth into larger granules which
would be broken by a chopper blade to control the growth. Mixing
continues even after liquid addition was stopped due to wet mass-
ing. In this granulation, the amount of binder and the end point of
wet massing were highly critical to control the desired granule
attributes viz., GSD, strength, density, porosity etc. It was also
observed that for binders like water, the granule attributes could
be controlled through experimental and design variables mainly
impeller speed and massing time while when using binders like
micro-emulsions, they would be difficult to be controlled leading
to larger GSDs than desired.
3.2.2. Fluid bed granulator
In FBG, the ingredient powder was initially charged into the
fluid-bed system and air was fed to the column through the bottom
of the granulator. It essentially consists of nozzle, solution delivery
system and compressed air to atomize the liquid binder. A distrib-
utor plate helps in retaining the powder in the bowl, while filters at
the top of the column allow air to pass, but prevent solid particles
from escaping. Once the powder was fluidized, binder solution was
sprayed as liquid droplets using atomization nozzles onto the fluid
bed to initiate coating and agglomeration forming granules. These
were then dried by passing air through the system [86]. The FBG
equipment was initially operated in a batch mode till the granula-
tion was complete before switching to continuous mode where the
powders were introduced via an inlet valve and simultaneously
discharged through an outlet valve. The inlet air was segmented
allowing for better process control than the HSWG. FBG process
was versatile and integrated though complex as mixing due to agi-
tation of the fluid bed helps in both agglomeration and drying of
the particles [87]. Granules produced by FBG process were
reported to be more porous, less dense and more compressible
than those produced by HSWG process [88–90]. FBG was process
intensified as spraying, size enlargement and drying were carried
out in a single unit [91].
Papiya et al., [92] proposed a heat-mass transfer analogy equa-
tion useful for the design of these granulators linking the heat coef-
ficient h, particle diameter Dp and fluid flow rate mo as
hDp ðm =AÞD2p k
¼ ð2Þ
Kp 6Lht Kp ðTg  Tl Þð1  emf Þ
(where, h is the convective heat transfer coefficient of the particle,
kp denotes the conductive heat transfer coefficient of the particle,
Dp is the diameter, e is the porosity k denotes latent heat of vapor-
ization, Lht is the Entry length, Tg is the inlet gas temperature, Tl is
the liquid temperature, A denotes the area of bed, mo is the evapo-
ration rate of liquid.)
There were two main configurations of FBG namely top spray
and bottom spray/Wurster granulator. The later was more effective
for tablet coating in pharmaceutical applications in which a cylin-
drical draft tube with a segmented air distributor plate was placed
below. The tube section contains both wetting and drying zones
with acceleration induced through venture effect leading to faster
and consistent granulation with low attrition [93,94]. To address
the main challenges of FBG like smooth handling of fine granules
and attrition, rotary fluidized bed with large centrifugal forces cre-
ated by rotating air distributor was developed. But it suffers from
loss of granules due to entrainment which could be minimized
using granulators with tapered geometry [95–99] which were yet
to be scaled-up. FBG could also be operated in a continuous fashion
using horizontal moving bed granulators/driers (e.g. Glatt GF ser-
ies, Niro Vibro-Fluidizer, Heinen Drying Technologies) used in
dairy, chemical and food processing industries. A continuous FBG
consists of a chamber divided into different functional sections
which were not mechanically separated from each other [100].
The process was essentially a plug flow with some back mixing.
The vital parameters affecting the performance of an FBG were
movement of particles, addition of the liquid binder and drying
capacity of the air. Thus, efficient granulation in a fluid bed system
could be achieved by thorough mixing of particles and formation of
strong liquid bridges which could dry easily. A binary design (two
fluids) nozzle was found to give a wide droplet size distribution,
which would eventually result in homogenous granules [101].
Other factors that were found to influence FBG were amount and
spray rate of binder liquid, spray nozzle location, binder droplet
size, atomization pressure, temperature of fluidizing air, pressure
drop across the bed, aperture area of air distributor plates and
interval between bag shakes of filters. Larger amounts of liquid
binder were used in FBG vis-a-vis HSWG to compensate for any
loss of binder by evaporation [46,63]. Aulton et al., [102] found that
better granulation and PSD were achieved when lower fluidizing
air temperatures, dilute binder solutions, and higher spray rates
were used. It was also reported that PSD of the granules could also
be improved by optimizing bag shake times [103]. Also, increasing
the inlet temperature could result in spray drying leading to faster
solidification of liquid bridges forming loose granules with low
fractal dimensions [104]. It has been reported that the use of high
binder mass fraction in FBG led to increase in the agglomeration
rate [105,106]. A relation for spray conditions as a function of the
major operating variables has been given by Litster et al., [107].
Spray flux w (a dimensionless quantity) defined as:
3Vo
w¼ ð3Þ
2Ao dd
(where Vo is the volumetric spray rate, Ao is the Spray area and dd
denotes the average droplet diameter) – is a strong function of pro-
cess parameters. Larger spray flux would mean that the rate at
which drops cover the exposed bed area exceeds the rate at which
the bed surface was renewed and as a result drop coalescence
occurs on the powder surfaces.
Another relation which explains the influence of process
parameters and formulation properties is the dimensionless drop
penetration time sp, which is given
tp
sp ¼ ð4Þ
tc
(where tp is the time taken for a drop to fully penetrate the powder
bed and tc is the time taken for the exposed surface of powder to
circulate back to the spray zone.)
If this parameter was large, a drop could coalesce with another
drop before it penetrates into the powder bed and leaves the spray
zone, even at low dimensionless flux. Thus, the dimensionless drop
penetration was a measure of both thermodynamic and kinetic
interactions between liquid binder and powder used for granula-
tion. FBG had other advantages viz. avoiding milling operation
after granulation, producing granules of higher porosity and nar-
rower size distribution and operating in a closed loop auto cleaning
mode [105]. The disadvantage of this however was its low repro-
ducibility of products which is a serious concern in the pharmaceu-
tical industry [108,109].
3.2.3. Spray drying granulation
Though mostly continuous, this granulation process could be
operated in batch mode too in which size enlargement and drying
were carried out in a simple equipment [109]. According to Harald
Stahl et al., [110] the API in pharmaceutical processing could ini-
tially be produced as granules in the primary production line using
spray granulation requiring only blending with suitable excipients
 P. Suresh et al. / Chemical Engineering Journal 328 (2017) 785–815
for direct compression in secondary processing. All the ingredients
could also be mixed to form slurry or a solution and spray drying
could be carried out in a single step to form the final granules. In
this process, liquid feed was atomized at the top of the tower
and after evaporation was completed, the particles were separated
in a cyclone and reintroduced into the drying chamber. Here they
come in contact with the wet droplets and agglomerate, and after
reaching a particular weight (based on the air velocity), fall down
to the bottom for further processing. The conventional one-stage
spray-drying though a continuous process was not suited for
tableting purposes owing to poor flow properties of the granules
produced [111]. Though, the granules produced this way tend to
be dense and resistant to abrasion, (since they have grown in
layers), the continuous granulation by spray drying method
needs further processing or adding another processing unit to
get all the desired attributes of the granules [112,113]. In a
continuous spray granulation, the solutions, suspensions or melts,
were sprayed into a fluidized bed system which would then
evaporate due to heat exchange to form solid starter cores. These
cores develop layers of hard coating by spraying liquids/binders
continuously in a fluidized bed. The split velocity, nature, viscosity
and amount of the binder liquid, location and design of spray
nozzle were found to be vital parameters in this process. The
residence time of the powder too affects the mechanical strength
of the granules, where longer residence times lead to denser gran-
ules [114].
3.2.4. Twin screw granulation
This process very commonly employed in chemical and process
industries has been gaining importance in pharmaceutical applica-
tions too due to its easy scalability, simple maintenance, high pro-
duct quality and easy integration with drying, milling and tableting
operations. Twin screw granulator (TSG) or extruder has a chamber
housing two parallel co-rotating screws fed with feed material and
binder introduced at specific locations to form granules. This screw
block chamber could be divided into three elements i.e. conveying
element with low shear to transport material to the mixing zone;
kneading block acting as primary mixing zone imparting high
shear, energy and compaction forming dense and large granules
and comb mixer element acting as secondary mixing zone. The
comb mixers act as flow distributers and generate forward or
reverse flow to provide better mixing, moderate density of gran-
ules (higher than that provided by conveying elements but lower
than kneading elements) thereby controlled friability. TSG was
influenced by many parameters viz., kneading block and angle,
screw length, cross sectional area, L/D ratio, rotational speed and
binder introduction [115–117].
Early usage of extruders for granulation was in spheronization,
which was done mostly using single screw [118,119]. TSG was first
implemented in pharmaceutical research by Gamlen et al., [120] in
1986 to produce paracetamol extrudes [115]. It had been reported
by Keleb et al., [121–123] that granules produced by TSG exhibited
improved properties such as increased tensile strength, improved
disintegration, and friability when compared to those produced
by HSWG. Melkebeke et al., [124] found that adding an extra con-
veying unit after the kneading block improved the granulation
yield by reducing oversized agglomerates. The kneading block in
granulation was generally used to achieve compaction and then
fragmentation [4,125–130]. Djuric et al., [126] and Thompson
et al., [128] found that while screw design strongly influenced
granule and tablet attributes, angle of kneading elements did so
on the PSD and conveying capacity with marginal influence on
strength of granules [115]. TSG studies were reported on the
changes in temperature for uniform and non-uniformly wetted
powders. These temperature changes were found to be around
791
5–15 °C in the former and around 70 °C in the later [131–134]
depending on flow rate, screw speed, L/S ratio, binder concentra-
tion. Residence time distribution (RTD) studies were important in
design, development and scale up of twin screw systems. Typically,
higher mean residence time lead to better distributive mixing
while complex rheological mixtures increase design complexity.
Mean residence time decreased with increasing screw speed due
to increased conveying capacity of the screws. Similarly, mean res-
idence time decreased with increase in the material feed rate
[115]. In TSG, an increase in viscosity and concentration of binder
reduced its requirement to produce granules with a mono-modal
size distribution [135]. A scale independent wet granulation pro-
cess map for a TSG was presented by Kumar et. al. [116], who also
studied the effect of various parameters such as L/S ratio and
energy input on PSD. It was seen that high number of kneading ele-
ments and increased barrel temperature resulted in less fines,
more oversized agglomerates and less friable granules. The study
also identified binder addition method as a critical parameter in
achieving the desired RTD [129].
On the basis of the above discussion, different granulation tech-
nologies have their own merits and demerits. Low/High shear
Granulators in batch mode were suitable for tablet manufacturing
due to better drug distribution, shorter processing times, less
amount of binder required, effective process control and lower
energy consumption per unit mass. But it suffers from drawbacks
like poor mechanical properties of granules due to short residence
times, chemical degradation of thermally sensitive materials and
lump formation due to over wetting. FBG, an integrated and
intensified option offers closed material handling decreasing the
exposure of the material but it demands high energy,
larger amounts of binder and efficient process control. Spray
granulation required even higher energy per unit mass and pro-
vided improper separation of wet and dried granules. Hence it
was deployed in the pharmaceutical industry for batch applica-
tions only. Table 1. summarizes all the granulation technologies
in terms of the mode of operation, process, scale, critical process
and design parameters, granule attributes, yield and binder, merits
and demerits.
4. Novel granulation techniques
Conventionally binder in liquid state was employed in granula-
tion process. Of late, novel granulation techniques based on the
physical state of binder were developed viz., super critical granula-
tion (SCG), foam granulation (FG), steam granulation (SG), reverse
phase wet granulation (RPWG) etc. In SCG, super critical fluids
(SCF) (at super critical thermodynamic conditions) like CO2 were
employed as they possess both liquid and gas like properties and
are thermodynamically favourable, non-toxic, chemically inert,
cheap, consume less energy in granulation due to shorter process-
ing times [137,138]. They produce granules of uniform PSD with
minimal or no use of solvents in fast and effective manner and
could be employed for heat and moisture sensitive materials, But
it demands the design of granulator operating under supercritical
conditions with total safety which is the primary challenge of this
option [139,140]. The foam granulation developed by Dow chemi-
cals in 2003 employs binder as foam forming granules of desired
attributes [141]. It has advantages such as uniform distribution,
larger surface area of wetting with minimal amount of binder
and simple design modification in terms of foam generator. This
technique was successfully employed in TSG with latest studies
on scale up and parameter sensitivity reported on HSG and FBG
too [142–146]. Tan et al., [147] found that in HSG while high foam
quality and impeller speeds gave fine PSD, lower values of those
 792
Table 1
An overview of wet granulation technologies.

Granulator and Critical Design Parameters Granule Attributes Applications Scale Yield%, Binder Merits Demerits Ref.
Mode wt.%
Low/High Shear Design geometry of granulator Low Shear: Fluffier and more Low Shear: Heat Smaller residence time, and [13,44–47,50,136]

P. Suresh et al. / Chemical Engineering Journal 328 (2017) 785–815

Mixer and impeller and chopper shape, porous granules. sensitive Materials. Scale up of 99–99.5% High drug loading, improved possibility for mechanical
Batch size and speed. High Shear: Less Fluffy, High Shear Highly High Shear 8–15% dissolution and short degradation and thermal
porous and lower friability. Cohesive Mixer. is difficult. processing time. Requires degradation of fragile and heat
PSD: 100–800 mm (<1800 L) lesser binding liquid and sensitive particles.
energy than FBG. Unsuitable for moisture
sensitive materials as over-
wetting could lead to lumping.
Nozzle design and location. Highly Porous, less dense and Heat sensitive Closed Material Handling Low reproducibility and [86–89,93,95]
Fluid Bed. Geometry of the granulator bowl. more compressible than Materials, tablet Easy Scale 99% Low energy requirement requires more liquid solution.
Batch Fluidizing air temperature and HSWG. coating and for raw up for 30– 8–30% when drying large surface
design of air distribution plate. PSD: 120–800 mm materials with 2000 area.
similar PSD. tonnes
Residence time, fluidizing Uniform particles with good Tableting when Single equipment for More losses during start up and
Fluid Bed. velocity, location and spray rate flow and dissolution dissolution is a Production >99% granulation and drying. shut down. High energy
of nozzle, Mixing, wetting and characteristics. main criteria Scale. 15–30% requirement.
Continous drying zone distribution. High porosity and narrow
PSD.
Spray Granulation Residence Time, Fluidizing Very poor flow properties. Easy Scale Single equipment for drying Improper separation of wet and [109–111,113]
Continous Velocity, Spray rate and Binder PSD: 150–300 mm up, >99% and Granulation dried particles and very high
properties. Production 100% energy requirement
Scale
Screw design, kneading angle, Irregular shapes but Good for heat Higher API loading possible Time sensitive and mechanism [115,116,121,122]
TSG binder properties, residence time, consistent strength. Very sensitive materials. Production >98% with a most combination of is not properly understood.
Continous and barrel temperature. Mixing, good dissolution properties scale 15–50% API’s in any ratio.
wetting and kneading zone due to large number of pores. Moderate energy
distribution. PSD: 800–2000 mm requirement.
 P. Suresh et al. / Chemical Engineering Journal 328 (2017) 785–815 793

gave coarse PSD. Further studies were needed to understand the

[141,143,155]

[136,153,154]
impact of critical process variables and hydrodynamics and scale-

[137–139]

[150,152]
up [148,149]. Recently SG was gaining attention in which steam
was employed instead of liquid water as granulation liquid by

Ref.
which distribution was more enhanced, fast and uniform leading
to granules of spherical shape (due to large surface area) and with
high dissolution rates [150–152]. The limitations of this process

Can be integrated easily

with a HSG, (Requires a
Adaptability/Feasibility
were energy needed to produce steam and suitability to systems

generator and can be

with only water as binder. In reverse phase wet granulation, the

Requires only foam

steam generator)
powders were dispersed in a controlled manner onto an agitated
binder solution [153]. Though this requires large amount of binder

Very Low

Very Low
solution, in recent years, reverse phase wet granulation has been
gaining interest with few studies being reported as an alternative
to conventional granulation [33,138]. The effects of Smax (Liquid
Saturation  dimensionless measure of liquid content) and binder
liquid viscosity on the granule attributes in RPWG for hydroxyap-

Requires special high pressure

Cannot be used for moisture

atite granules have been reported by Wade et al., [153,154]. But

Requires more binder than

Low porosity and low PSD
more rigorous process, integration and scale up studies are
required to be done on RPWG.

High energy penalty

conventional mode
Table 2 summarizes the novel granulation techniques as dis-

sensitive drugs
cussed above.

equipment
Demerits
5. Characterization tools for various granule attributes

Characterization tools play a crucial role in assessing granule

Reduced Energy requirements and can be

attributes and thereby the granulation process. These could be

Uniform wetting and high surface area

Improved dissolution properties and
classified as offline and online/inline tools depending upon

applied to heat sensitive and water

High surface area during wetting

whether the assessment was done after or during the process,

High dissolution characteristics

the latter being more rigorous. With the transformation of batch

Lower Binder requirement

to continuous processing in pharmaceutical applications that

sphericity of granules.
needs effective process control, the online tools were becoming
sensitive materials

more critical. FDA is also encouraging the development of process

analytical technologies (PAT) to acquire and assess data online and
build quality by design (QbD) by a thorough understanding of var-
ious input variables, their interaction with one another and their
Merits

influence on the granule attributes and end quality. The combina-

tion of Design space-Design of Experiment approaches is being
used to understand the complex interactions between the vari-
Uniform Binder distribution and

ables [15,156]. QbD’s motto was ‘‘quality cannot be tested into Spherical Granules with Larger
Other properties are similar to
Other Properties are similar to

products; it should be built in or should be by design”. It states that

conventional granulation

conventional granulation

quality should be built into a product by a thorough understanding

Granule Characteristics

highly porous granule

of the product and the manufacturing process with all its risks and
ways to address them [157–160]. Thus it lays emphasis on thor- Spherical Shape
ough process knowledge as a criterion rather than product quality
Uniform PSD

surface area
techniques.
techniques

Lower PSD

and attributes.

5.1. Offline/end product characterization

Use of steam as a granulating
Use of foam as a granulation
Use of SCF as a Granulation

Particles are in a controlled

There were numerous offline/end product characterization

manner dispersed into the
An overview of a few novel wet granulation techniques.

tools to assess various granule attributes viz porosity, bulk den-

sity, flowability, strength, surface area and PSD. Granule porosity
General Description

was defined as the ratio of void volume to total volume that has
a bearing on their strength and dissolution characteristics of
tablets. Granule flowability for easier handling was given by Carr
index, a ratio of bulk density to tapped density. Higher the index,
Liquid

liquid

liquid

liquid

lower is the flowability. Generally, Carr index of <15 is good for

tableting, 25–30 for tablet filling. Orifice and shear cell tech-
niques were also employed to assess granule flowability. These
Reverse Phase Wet
Steam Granulation
Foam Granulation

methods help in quantifying the cohesiveness of the granules

and the associated flow properties. Bulk density could be esti-
Granulation

mated using percentage bed porosity. Direct crushing and gran-

Technique

ule friability tests were used to measure granule strength

SFG

except for sizes less than 40mesh. In the pharmaceutical indus-

Table 2

try, pore structure of granules measured by BET and mercury

porosimetry methods is very critical as it is directly related to
794 P. Suresh et al. / Chemical Engineering Journal 328 (2017) 785–815
the dissolution rate. PSD/GSD is measured using sieve analysis,
laser light, scattering or optical microscopy and SEM. LOD, Karl
Fischer or water activity methods were employed for estimating
moisture content which is a vital property to be controlled to
have desired granule attributes like flowability, pore structure,
density and ease of tablet formulation [161,162,163]. Hence
moisture content should be closely monitored during granulation.
Crystallinity which assesses the physical stability of the APIs dur-
ing granulation was measured with variable temperature XRPD
(X-ray Powder Diffraction). Ring shear tester has been employed
to measure the flow properties of various powders and granules
[163]. The effects of particle size, morphology and particle den-
sity on flow behaviour have been reported. It was found that
spherical morphology, larger particle size and higher density
were conducive to improved flowability.
Table 3 compares various offline characterization tools available
for estimating different granule attributes.
5.2. In-line characterization
Various in-line characterization tools to monitor the granula-
tion process effectively and continuously at a micro-level to
achieve QbD were developed like capacitance measurements
[181], optical fiber systems [182], image acquisition and analysis
[183,184], Raman spectroscopy [185], Near Infra-Red spectroscopy
(NIR) [186–189], magnetic resonance imaging, MRI [190], micro-
wave, stress, vibration, positron emission measurements
[191,192], effusivity measurements [193], acoustic sensors etc.
High speed imaging was employed to assess the PSD and granula-
tion behaviour (using eyecon camera) with some limitations of
fouling of optic surfaces and image resolution issues with fines
and oversized fractions [194–196]. Corvari et al., [197] used a
capacitive and resistance sensors with microcrystalline cellulose,
lactose and HPMC granulation in a vertical high shear granulator
to measure density and moisture content. A latest development
in nascent stage was ECT (Electrical Capacitance Tomography) that
couples capacitance measurements with imaging and involves
computational complexity. Among spectroscopic methods, NIR
and Raman spectroscopy were the most commonly employed tools
to understand the mixing state and composition of the granules
including moisture content [198–200]. They were reported to be
successfully integrated not only with fluidized bed and twin screw
granulators but also high shear type [201–205]. When used in
combination, they become a powerful tool for a comprehensive
granulation characterization. As each has their own limitations of
applications as NIR requires a thorough calibration while the other
cannot scatter water [206,207]. Focused Beam Reflectance
Measurement (FBRM) though expensive technique, was used in
fluidized bed granulators to study the growth of granules in real
time [208–210]. This technique employs a probe at a given velocity
to emit focused beam of laser light which would be back scattered
by the particles. This backscattering was used to estimate the par-
ticle chord length distribution and thereby PSD [211,212]. The
integration of this tool with a granulator was complicated and
expensive requiring extensive set up of probes and rotating lens
inside the granulator [213]. Spatial filter velocimetry (SFV) consist-
ing of a laser beam and optical fibers could be used to simultane-
ously estimate the chord length of the particle, chord length
distribution and the particle velocity [214,215]. Using the shadows
generated onto optical fibers, the velocity and the chord length
were appropriately estimated [216–218] in both online and offline
modes as an effective alternative to cumbersome sieve analysis.
Huang et al., [219] have developed a multivariate statistical control
method based on SFV measurements for a fluid bed granulator to
increase the range of measurement which could also be attempted
to other granulators too. Microwave measurements were evolving
as non-invasive and accurate measures of the moisture content
[220] but with associated challenges arising from the changes in
bulk density and particle size which restrict estimation of moisture
content. Acoustic emission sensors were used to understand the
physical and chemical properties of the granules formed. During
granulation, particle-particle or particle-chamber collisions and
friction generated vibrations were picked up by the Acoustic emis-
sion (AE) sensors giving acoustic spectra from which the process
relevant information [10] could be extracted using calibration
and chemometric techniques [220]. Several studies have success-
fully implemented AE sensors in fluidized bed granulators, both
at small and semi-industrial scale [221–223]. Though the tech-
nique was non-invasive and inexpensive, the need for extensive
calibration and modelling techniques in extracting the relevant
information made it still unexplored at the industrial level. Stress
and vibrational sensors have also been successfully utilized to esti-
mate granule growth, predominantly in HSWGs [224–227]. The
stress fluctuations were correlated to granule growth while the
vibrational spectrum has been successfully associated with size
distribution and density. These tools have since then been used
to estimate end point deduction in granulators [225]. However, it
must be noted that the results and accuracy of the sensors were
strongly related to employing the correct sizes of sensing elements
[228]. Velocity and flow measurements could also be done using
tools such as Laser Doppler Velocimeter (LDV) and Phase Doppler
particle analyser (PDPA) [229,230] to understand the granulation
behaviour in SG and FBGs [231–233]. These measurements could
also be employed in validating various DEM-CFD models [234]. It
has been suggested that the combined application of LDV and
PDPA with particle imaging tools could provide better process
understanding [235]. Positron Emission Particle Tracking (PEPT),
though expensive but effective, could be employed to estimate
the flow behaviour and RTD in a granulator as an alternative to
other imaging tools [236,237]. This method needs further studies
with selection of tracer similar to bulk material playing a signifi-
cant role in its functioning [238,239].
Table 4 summarizes and compares various online characteriza-
tion tools with their merits and demerits. Table 5.
6. Modelling and simulation
Modelling of a process always enables to have a better analysis
of the system dynamics and then formulate an efficient control
strategy to enhance the efficiency of the operation and scale-up
more effectively if required. Model based approach is always handy
when plant level experimentation would be labor and capital inten-
sive to understand the multi facets of a dynamic process like gran-
ulation. Simulations which could be done at macro (overall flow
behaviour), meso (ensembles of granules and particles) and micro
(individual granules/particles) scales were done to understand the
granulation process. Equations based on continuum and volume
averaged bases were solved for macro and meso scales. Numerous
studies were reported on modelling and simulation of wet
granulation for gaining a better understanding of intricacies in
the process, mechanism and therefore achieve effective process
control and product quality [240]. Such models help in assessing
process conditions to be employed to get the desired output
[241,242]. Also modelling studies facilitate to achieve efficient
recycle ratios without rigorous experimentation. Until 2002, the
recycle ratios typically obtained in the wet granulation process ran-
ged between 1–2 and 1–6 [243], which need to be refined through
efficient model based control systems and suitable measurement
Table 3
Overview of various off line characterization tools.

Granule Attributes Description Characterization Tools Working Principle Relevant Equations Ref
Physical Characterization of granules
Granulation Porosity Porosity is a measure of number of voids in a i. Carr Index i. The Carr Index indicates the packing of Carr Index ¼ 100  ðPdAdÞ
Pd
[164,165]
granule or powder bed. Porosity helps define granules and to estimate the ease of
the granule structure. granulation flow.
%GP ¼ ð1  qqEV Þ

P. Suresh et al. / Chemical Engineering Journal 328 (2017) 785–815

ii.% GP ii. Used to find the relative porosity
s

Bulk Density Mass per unit volume of loosely packed bed of % bed porosity Indicates how much compression is needed to %bedporosity ¼ ð1  qqBD Þ
s
granules remove porosity
Granule Flowability Flow of granules or rate of discharge of i. Orifice technique i. Flow rate during discharge is measured. [166–168]
granules ii. shear cell ii. Shear force required to move one layer [169]
against a stationary lower layer to characterize
the powders in consolidated form to change
from non-flow to flow condition.
Granule Strength i. direct crushing test i. records the granule crushing strength. [170–172]
ii. granule friability# ii. Attrition method using a Roche friabilator to [173–175]
measure granule friability.
Granule Surface Area i. BET gas absorption method i. total air to solid surface area of a granulation [176]
(SSA) can be measured.
ii. RVS RVS ¼ q1 =As
t

Granule Size and Size
Distribution
Chemical Characterization of Granules
Moisture Content Free water state causes instability, poor flow,
mottling, both softening and hardening of
tablets and capsules shells, issues with changes
in dissolution and bio availability.
API uniformity Composition of granules should be uniform.
Crystallinity Assess the physical stability of the APIs during
granulation.
i. Particle size can be measured by sieve
analysis, laser light, scattering or optical
microscopy.
ii. Granule morphology-SEM
i. LOD
ii. KF- Karl Fischer method
ii. water activity
Sieving approach
Modulated temperature, XRPD
Particle shape- relationship of volume
weighted mean in laser particle size analysis.
i. TGA is a method of LOD. [177–179]
ii. Measures total water in sample
iii. Determines the moisture content that is
present in free state to evaporate.
A uniform composition of API in each sized
fraction is expected
It is used to identify the crystalline form of a [180]
pure substance.

795
 796
Table 4
Overview of various online characterization tools.

Technique Attributes Working principle Merits Demerits Ref

NIR spectroscopy Granule moisture Water absorbs some of the NIR spectrum energy. The Accurate moisture composition data Extensive calibration required before [201–203]
contentCharacterizing degree of energy absorbed indicates moisture content when calibrated properly application
material flow and mixing

P. Suresh et al. / Chemical Engineering Journal 328 (2017) 785–815

Raman Spectroscopy Granule Each component possesses a distinct Raman shift which Accurate measurement of composition Extensive calibration required before [185,206,207]
compositionPrimarily API allows easy identification of component composition in of APIs which otherwise cannot be application
composition granules known in realtime
FBRM Measure changes in particle Based on the scattering and reflectance time of laser beam Accurate study of granule size Small measurement zone and difficult to [208–210]
sizes integrate technology into existing
granulators
SFV GSD and velocity Based on the shadow formation on the optical fibers and the Higher measurement zone and provides Difficult to integrate with existing [213,214,216]
subsequent pulse generation simultaneous velocity and size granulators
measurements
Microwave Granule moisture content Based on the degree of absorbance of microwave spectrum Changes in bulk density and particle size [220]
measurement restrict accurate measurement of
moisture
Acoustic Granule size AE sensors are used to detect the vibrations and other Inexpensive Extensive calibration and modelling [221,222]
measurements Granule water content acoustic spectra generated from particle-particle and Can be used for real time detection of studies required to implement
particle-equipment collisions end point of granulation operation.
Capacitive sensing Granule moisture content Based on the variations in capacitance with moisture Difficult to incorporate and integrate with [197]
Granule density content and density variations existing granulators.
High speed imaging Measure changes in particle High speed imaging using suitable optical aides Direct measurement of size and flow Frequent fouling of optical surfaces [194–196]
sized trends
Laser Doppler Instantaneous velocity of Principle of Mie theory and evaluation of scattered light Non- intrusive and highly accurate Obstructed particles are excluded from [229,230]
velocimetry granules and Flow frequencies evaluation restricting measurements to
behaviour only the exposed layers.
Stress and vibrational Granule Growth, GSD Stress spectra caused by the granules onto the probe/ Capable of intrusive and non-intrusive Require a lot of equipment modification [225,228]
measurements sensor due to collisions vary with granule growth setup for integration with existing granulators
Extensive calibration and studies required
before successful implementation
PEPT RTD and flow behaviour Based on deduction of radioactivity of a tracer compound Non-intrusive technique Limitations of imaging techniques aren’t [236,237]
Accurate real time trajectory of particle there and can be sued for highly dense
flow can be visualized systems as well
 P. Suresh et al. / Chemical Engineering Journal 328 (2017) 785–815
protocols. This would also bring about better process designs, oper-
ation and process evaluation, which would eventually lead to
reduction of both cost and time while implementing the process
[244–247].
Wet granulation occurs in three steps viz., wetting and nucle-
ation, consolidation and growth and attrition and breakage, the
former affecting the flow dynamics and thereby end product qual-
ity significantly. Till recently, only limited research was available
on the effect of binder addition, binder distribution and nucleation
on granule attributes. It was predicted that average granule size
had a direct linear relation with spray rate and inverse relation
with powder bed velocity [248]. The increase in spray surface area
was found to narrow down the PSD like powder bed velocity [249].
Studies also indicated that the liquid binder drop size along with
spray rate had a direct relation with granule size in the early stages
of growth [250]. Dimensionless spray flux was used as a measure
of the density of droplets that was used to predict the controlling
mechanism of nucleation along with dimensionless drop penetra-
tion time, a ratio of penetration time of drops in the powder bed
to the circulation time of the powder to return to the spray zone
[107]. Monte Carlo model was developed and experimentally vali-
dated to predict the extent of drop overlap in the spray zone to
produce single nuclei but could not extend to the full nuclei size
profile [251]. This work was extended to develop a nucleation
model to investigate the effect of design and operating parameters
of the nucleation process viz., binder spray characteristics, the
nucleation area ratio between droplets and nuclei and the powder
bed velocity on nuclei size distribution. It was found that nucle-
ation area ratio had a strong influence on nuclei overlap and the
distribution of binder liquid mass led to larger extent of droplet
overlap in the spray zone. It was also found that binder liquid flow
rate and powder velocity had the similar effect on droplet density,
thereby affected nuclei size distribution while droplet diameter
influenced the number and size of droplets sprayed without much
effect on nuclei size profile and total volume of nuclei. The nucle-
ation area ratio on the other had did have its influence on the total
volume of the nuclei formed and the controlling nucleation mech-
anism. This nucleation model could replace nucleation term in 1D
population balance models that describe wet granulation process
[252]. These uni-dimensional population balance models focused
on granulation mechanisms with little emphasis on nucleation
were traditionally employed to predict PSD only with no study
on the effects of particle porosity and moisture content. These lim-
itations were overcome later by the development of multidimen-
sional population balance models.
Population Balance model (PBM) and Discrete Element model
(DEM) were the most widely used models for wet granulation
[253–256]. PBM takes the particle properties into account and
defines how populations of separate entities develop specific
properties. It was more often used to simulate wet granulation
as it captures multi-dimensional properties viz., size, liquid con-
tent and porosity [257,258]. They however rely on fitting
unknown parameters and thus were restricted to an experimen-
tally designed space [259–262]. On the other hand, DEM (origi-
nally proposed by Cundall et al., [263]) considers, each particle
as a discrete entity where the trajectories of the particles were
tracked and collisions between them modelled. This approach
however was computationally rigorous and expensive at larger
scales [264]. DEM captures these particle scale behaviours with-
out inherently correlating these to the process scale changes
[265,266]. Early models in this approach only considered granule
volume as a particle/granule property, incorporating only coales-
cence as a transformation [267,268]. The advanced models con-
sider three or more internal co-ordinates and also incorporate
797
other transformations such as liquid addition, breakage, com-
paction and reaction [53,258,269,270]. There were two
approaches within DEM itself viz., the hard-sphere approach
and the soft-sphere approach which have been extensively
reviewed over the past decade [271–275]. While the hard-
sphere method assumes particles to be rigid with the collisions
being binary and instantaneous, the Soft-sphere model assumes
multiple contacts at any instant of time which were not instanta-
neous. Hence the former was not applicable to highly dense gran-
ulation processes where the collisions were non instantaneous
with multiple contacts which were better treated by the soft-
sphere model. In soft-sphere model, the position, velocity, accel-
eration of each particle was obtained from Newton’s second law
of motion [263]. Here the contact forces resulting from the
particle-particle and particle-wall collisions were modelled by a
spring, dash-pot and slider. However, one striking difference
between PBM and DEM was the treatment of rate processes.
DEM simulation could not independently simulate particle size
and property changes resulting from sub processes in wet granu-
lation while PBM lacks in capturing the granulation behaviour
without empirical parameters inherent to its kernel [276]. Hence
coupled/hybrid PBM-DEM model was developed to represent wet
granulation comprehensively at all scales ranging from micro to
macro (micro-meso-DEM; meso-macro-PBM) with a further need
to validate it experimentally [277–280].
One of the major challenges in modelling studies was incorpo-
rating various rate processes viz, coalescence, aggregation, break-
age etc into the model using appropriate kernels that take into
account different types of collisions, the factors responsible and
their impact on the granulation process, mechanism and the gran-
ule attributes. The coalescence kernel, a measure of frequency and
success of binary collisions, was mainly dependent on collision
probability and successful aggregation or rebounding after colli-
sion [2,268]. Adetayo et al., [167] found that the coalescence kernel
incorporation was a major challenge in both PBM and DEM. A mod-
ified population balance model for high shear wet granulation was
developed by splitting the coalescence kernel into two parts viz.,
collision frequency and collision efficiency. Four kernels on colli-
sion frequency were analyzed and found that ETM and EKE kernels
could successfully explain the granulation processes at high and
low impeller speeds respectively. It was also found that accounting
liquid saturation was essential for collision efficiency function to
show mostly, s-shaped trend [270]. Several studies on coalescence
and aggregation kernels were reported to understand the
functional dependency of the growth rate on material and process
variables, a very important parameter in process modelling
[267,281–284]. Similarly, studies have also been conducted on var-
ious breakage kernels that could be incorporated and modelled
[285–287]. Ramachandran et al., [285] had presented one such
mechanistic breakage kernel, considering particle-particle,
particle-wall, particle-impeller collisions and the contact area
formed upon collision. The breakage kernel, found to be a function
of powder and liquid binder properties yielded better results in
predicting the rate differences and PSD as compared to the empir-
ical and semi-empirical kernels. A multi-scale and multi-
dimensional population balance model (3D) using nucleation and
aggregation kernels was developed and validated for a batch gran-
ulation using drum granulator to predict the dynamics of the pro-
cess and granule attributes viz., size, fractional binder content and
porosity) of calcite/PVOH-water recipe under various operating
conditions. It was found that an improved dynamic tracking of
the granulation process could be done by incorporating binder
properties like viscosity, surface tension and solid-liquid contact
angle and powder properties like density, size distribution and
798 P. Suresh et al. / Chemical Engineering Journal 328 (2017) 785–815
surface asperities into mechanistic kernels which would facilitate
easy scale-up for new materials [288]. A 4D population balance
model (based on size, liquid binder content, solid composition
and porosity) was proposed for studying wet granulation by taking
granule composition as the fourth parameter to enable the study of
granulation of multiple components suited for pharmaceutical
industry that has excipients and APIs to produce tablets. It was
found that reduction of this multidimensional model to lower
orders by lumped parameter method was more efficient
that a full 4D model in terms of time saved and reduced complexity
involved, though with a marginal compromise in the accuracy of
the prediction [289]. A coupled CIP (constrained interpolation
profile)-DEM model was developed at meso scale to explain and
predict the nucleation stage of the wet granulation process in
which interfacial effects between solid-liquid-gas phases were
accounted besides the effect of surface tension on the fluid motion
[290].
Of late, CFD models that require large computation were being
developed to enhance the range of applications of the existing
models. Hybrid models of CFD with PBM and DEM were being
developed to complement each other but with long computational
times as they require large number of differential equations to be
solved simultaneously at a particle level tracking their spatial
movements [11,165,276,291–295]. To overcome this, three popu-
lar computationally economical approaches were implemented
viz., periodic section DEM simulation, simulation of larger and
fewer particles and reduced order models (ROM). In the first
approach, simulations were run for a particular segment of the
granulator that could be extended to other segments by symmetry
[296,297]. The second approach simulates the same problem for a
system of larger but fewer particles which was quite complicated
and required pre-determined particle density variations to main-
tain consistent momentum transfer between the particles. This
approach requires additional sensitivity studies before successful
implementation [298]. The third approach was relatively simple
computationally requiring only simple data fitting [299]. Though
few models like multi-component PBM, bi-directional PBM-DEM
were developed to explain TSG, more effective and diverse models
with less computation requirements were needed [300,301]. A
combination of CFD-DEM model at micro-scale was implemented
for wet granulation to understand the three phase behaviour in
the nucleation stage of wet granulation. The gas-liquid phases
and solid phase were solved by CFD and DEM respectively and
the combination of these solvers enable to understand the interac-
tion between solid and fluid phases. DEM approach has a major
role to play to bridge the gap between micro and meso- scales.
Capillary force models were incorporated into these CFD-DEM cou-
pled models to account for the capillary force exerted on the parti-
cles. Droplet penetration nature and penetration rate into the static
particle bed or a more realistic dynamic bed were studied by this
modification of capillary force models into CFD-DEM models. It
was found that droplet penetration was initially dominated by sur-
face wetting and was induced by capillary pressure when the dro-
plet was inside the particle bed [2]. To reduce the computational
inefficiency of DEM, there was a recent approach of training an
artificial neural network (ANN) using DEM results to relate particle
size, PSD and impeller speed to collision frequency. This ANN was
then coupled with PBM to form a reduced order model to describe
wet granulation process at a much higher precision in a reduced
time span [276]. A novel multi-scale bi-directional mechanistic
model with PBM-DEM coupling was proposed to explain twin
screw granulation process. This model showed sensitivities to the
screw element type and geometry as well as material properties
viz., binder viscosity, pore saturation and the process parameters
like screw speed, liquid-solid ratio. This modeling approach could
be used to establish a design space consisting of design, process
and material attributes to achieve QbD. From these studies, it
was clearly established that screw element design determined
the rate controlling process and product attributes i.e. mixing ele-
ments resulted in more aggregation, breakage and consolidation
than the feed screw that formed larger, denser particles. This
model could be extended to account for the presence of fine pow-
der particles and the mechanisms of nucleation and layering. Sen-
sitivities of product quality to the process design needs to be
established to lay out a path for implementing QbD and scale-up
[265]. Similar multi scale PBM-DEM bi-directional coupling models
taking into account of the collision frequencies and liquid
distribution were developed to explain the complex sub processes
(liquid addition and wet massing) of wet granulation and it was
found that there was an increase in particle size with time in line
with experimental trends. Liquid droplet distribution was also
simulated with this combination and found them to be
comparable with particle size i.e. each droplet wetting one particle.
Further work needs be focused on incorporating the nucleation
into this model [266]. Very recently, the coupled DEM-3D PBM
models were employed to predict the flow patterns and residence
time distributions in a continuous high shear wet granulator and
validated the same with the experimental data. The effect of shaft
speed on the flow patterns were predicted by this coupled model
and it was found that at low speeds, material gathers in the spray
zone which was very important for wetting, nucleation and
growth. Modelling a continuous granulator has always been a
challenge as it consists of all three rate processes viz., wetting
and nucleation, consolidation and growth and attrition and break-
age [302].
6.1. Summary of modelling and simulation
Modelling studies have been reported since very long starting
from PBM and DEM models and their modifications and combina-
tions. CFD in combination of these models also performed better
but with computational constraints. Future research efforts might
be in the direction of including particle level effects like attrition
and breakage, material composition and liquid spray into the
DEM model and optimizing the structure of the compartment
based model and PB parameters with algorithms like Genetic algo-
rithm, differential evolution for the PB model. These modeling
studies would be highly useful in optimal design and scale-up of
the continuous granulators.
There is a great scope of this modeling approach to be taken for-
ward to solve more complex problems incorporating particle scale
flux and velocity data from DEM to evaluate mechanistic rate
expressions in the PBM. Modelling studies have demonstrated var-
ious facts that continuous granulation though challenging was
more rewarding (due to its inherent benefits viz., enhanced and
consistent quality, increased throughput, reduced inventory,
manpower, clean-up time, raw material usage and storage,
reduced waste and improved safety); to use systematic framework
and scientific approach like QbD for commercialization of products
and processes; to develop computationally efficient numerical
methods that could solve multidimensional models; to calibrate
and validate the models rigorously and to develop more novel real
time measurement techniques to measure granule properties
in situ.
Tables 5 and 6 below compare various modelling approaches
used in wet granulation and different models employed in wet
granulation studies with their results.
Table 5
Physical modelling approaches of granulation process.

Model Equations Advantages Challenges Ref

PBM-Batch @Fðx;tÞ @ dxðx;tÞ Capable of simulating a large number of particles. Semi mechanistic approach due to lack of process [253,281]
@t þ @x ½Fðx; tÞ dt  ¼ Rformation ðx; tÞ  Rdepletion ðx; tÞ
@ @ dg @ Considers multi-dimensional and multi component knowledge.
@t Fðs; l; g; tÞ þ @g ½Fðs; l; g; tÞ dt  þ @s ½Fðs; l; g; tÞ dt 
ds

@ systems.
þ @l ½Fðs; l; g; tÞ dt
dl
 ¼ Raggr þ Rbreak þ Rnuc

P. Suresh et al. / Chemical Engineering Journal 328 (2017) 785–815

PBM-Continuous @ @ dg Capable of simulating a very large number of particles Semi mechanistic approach due to lack of process [86,256]
@t Fðs; l; g; tÞ þ @g ½Fðs; l; g; tÞ dt 
þ @s @
½Fðs; l; g; tÞ ds  þ @
½Fðs; dl
l; g; tÞ dt  and is equipped to handle multi component systems as knowledge.
dt @t
¼ Raggr þ Rbreak þ Rnuc þ Rf X o ðs; l; g; tÞ  Rf Xðs; l; g; tÞ well.
DEM-Batch/Continuous mi ddtv i ¼ m~ g þ~ Fp þ ~ Fw Follows a mechanistic approach. It is not capable of handling very large particles due [166]
dwi ~ ~ to computational limitations.
I dt ¼ Mp þ Mw
! !
!
v v
~ ¼ o þ½Fmc þ Fmw þ ~ g Dt
! !
!
~ ¼ wo þ½MI c þ MIw Dt
w
! !
F n ¼ knn  ðv r :~
nÞ~
n
! !
F t ¼  minðkn; jl F t jÞ:signðfÞ
Hybrid models combining PBM Capable of modelling complex dynamic mechanisms by There is difficulty in measuring the wet granule [279]
with DEM bridging the gap between micro scale and meso scale. yield strength, asperity height etc. Hence practical
implementation is difficult.
PBM with CFD Follows a mechanistic method and provides results for It is not suitable for dense particle system as it [11]
simplified results. ignores particle–particle interaction.
PBM with CM and DEM Provides improved accuracy of the PBM when particle There exist computational limits which restrict the [294]
flow is an important parameter. solution set.
Computationally economic modelling approaches
Periodic section DEM model Same equations as for DEM Suitable for preliminary estimations Approximate method and hence doesn’t yield exact [297]
(It considers one segment of the granulator and exploits Computationally economic and takes very less time results in most cases
the symmetry to expand solution segment to other
segments)
Larger and fewer particles Same equations as for DEM Suitable for preliminary estimations when PSD is known Requires pre calculated density function and [298]
methods (Considers particle to be few in number and larger in size, to be high additional sensitivity studies
thus limiting the number of individual particle
simulations)
ROM Data fitting method Less complicated than DEM models Statistical approach and thus may not be accurate. [303,304]
Computationally less taxing and several data fitting
techniques exist in literature

799
 800
Table 6
Modelling studies for various granulators.

S. No Model Type Granulator type Variables considered Scale Comments Ref

Artificial Neural Batch HSWG Impeller and equipment dimensions, 25 L, 100 L, 600 L, 65 L Neuro fuzzy logic technology was used to ascertain an experimental polynomial [305]
Network Impeller speed properties of wet mass and (with and without equation for the impeller power as a function of parameters considered. The model
proportion of granulation liquid. geometric similarity) worked for both geometrically similar granulators and the non-similar granulators.
Bi-directional PBM- Batch drum Equipment dimensions and rotational PSD data was calculated along with size distributions within the granulator system. [266]
DEM granulators speed, initial number of particles. liquid CFD and nucleation aspects were neglected.
addition time and liquid to solid ratio
Bi-directional PDM- Continous TSG Material properties, Equipment geometry, Model considers aggregation, breakage and consolidation.Shows potential to be used [265]
DEM liquid to solid ratio and process parameters. for scale up studies and achieving QbD
CFD Batch HSWG Equipment dimensions and impeller speed. 5L The granular flow was simulated based on the application of continuum based kinetic [306]
frictional model.Simulated results were validated using PEPT technique.
CFD Batch HSWG Equipment design and varying impeller A Eulerian approach to multiphase flows pattern and velocities was applied.The [307]
speeds. results were verified using high speed camera and image analysis software.
CFD-DEM Batch HSWG Equipment parameters, impeller speed, Lab scale CFD-DEM coupling is used to simulate drop penetration and penetration rate in the [290]
particle and liquid properties. bed. It was also used to simulate droplet impingement onto the dynamic particle bed.
DEM Batch HSWG Equipment dimensions, particle properties, 3L The results of the DEM analysis along with experimental verification (with the help of [308]

P. Suresh et al. / Chemical Engineering Journal 328 (2017) 785–815

impeller and chopper speed, Liquid to solid DOE) were used to analyse growth regime map.
ratio, different formulations.
DEM Batch HSWG Equipment parameters, impeller speed, 2 L, 112 L. The model was used to provide successful assistance to scale up from 2 L to 112 L. The [277]
model was used to determine the operating parameters at the different scales of
operation.
It was seen that constant impeller tip speed provided nearly constant magnitudes of
internal particle shear flow.
DEM (Soft sphere) Batch HSWG Equipment parameters, impeller speed, A novel boxing scheme and periodic boundaries was used to reduce computational [166]
powder properties. time along with experimental values for velocity flow fields.The DEM simulation was
used to develop a size-dependent compaction rate to be used further for PBM
simulations.
PBM Continous TSG Model included the aggregation and breakage sub-processes. [300]
PBM Batch spray Equipment design, Fluidization velocity, 100 g/h 300 g/h and Included and modelled the average wet surface fraction per wet particle and average [309]
fluidized bed binder properties, particle density 500 g/h mass flow rates success fraction with respect to dissipating kinetic energy (using stokes criterion.
Did not require any complicated parameter fitting.
PBM Batch HSWG Impeller speed, equipment dimensions, Provides a semi-mechanistic aggregation kernel that represents the influence of input [310]
Liquid spray rate. parameters on output quantities, based on sensitivity analysis.
Reduced number of empirical parameters are involved.
PBM Batch HSWG Impeller speed, equipment dimensions, Variable Pursued a DOE approach in modelling and can thus be used for scale up and [261]
liquid to sold ratio. operational studies.
Unable to track porosity of the particle.
Model requires further calibration.
PBM Batch HSWG Water amount, Impeller speed, wet massing 1 L lab scale. A DOE approach based on water amount, impeller speed, wet massing time; was [311]
time. undertaken and the most sensitive was identified as water amount.
The PBM model considered the agglomeration and consolidation process and was
calibrated using experimental results.
PBM Batch HSWG Equipment parameters, impeller speed, A volume based Mechanistic PBM was developed to study the size, porosity, binder [312]
water content, spray rate. content and pore saturation, with the results experimentally verified.
Chief limitation of the model is that it assumes perfect and ideal mixing.
PBM Batch HSWG Equipment dimensions, impeller speed, Simple model capable of predicting the GSD using an aggregation kernel. [255]
Liquid to solid ratio, binder properties,
powder properties.
PBM Batch HSWG Equipment dimensions, liquid saturation, 4L Four different collision frequency models were compared and the best models were [270]
impeller speed, binder properties. suggested based on impeller speeds. Additionally, power consumption and mixer
torque rheometry were used to estimate average shear rate.
PBM Batch HSWG Equipment dimensions, impeller speed, 10 L Compared two aggregations kernels and provided accurate results of PSD and liquid [313]
binder properties. binder content verified by experimentation.
PBM Independent Equipment Dimensions, liquid addition rate Different case studies were conducted considering a combination of aggregation, [314]
and amount, Mode of binder addition. breakage, consolidation, liquid and layering mechanisms and the results were
compared.
 P. Suresh et al. / Chemical Engineering Journal 328 (2017) 785–815 801

7. Kinetics studies
[276]

[291]

[264]

[315]

[316]

[276]
[302]

[304]
[11]

Kinetics of granulation gives an insight into the process mecha-

Considers the aggregation and breakage kernels as a function of the particle velocity.
Both PBM-DEM and PBM-Artificial Neural Networking was pursued and compared. A
ROM was used for the Artificial Neural Network and it was seen to be less intensive

properties and was tested with different scales of operation. Shows potential for scale

ROM was pursued using method of moments and Laguerre expansions using realistic
A compartmental model was developed with the aid of CFD to predict final granule
nism, the controlling regimes and to estimate the rate of the pro-

Computationally less intensive as compared to the PDM-DEM coupled model while

Particle attrition and breakage phenomena were not considered in the DEM model.

The model was able to successfully predict the PSD and bi component distribution.
Addresses the heterogeneity in a HSWG with respect to liquid content and particle
cess at various stages. Modelling and experimental studies have
computationally than PBM-DEM while providing reasonably accurate results.

Pursued a DOE approach in modelling and thus can be used for scale up and
Shows potential to be used as a tool for achieving QbD and process control. been reported for various types of granulators in batch and contin-
Effectively simulated the two phase flow and the results were verified with

uous modes of granulation, though limited on the later. Different

Artificial Neural Networking is used as a fitting model to facilitate ROM.

Artificial Neural Networking is used as a fitting model to facilitate ROM.

stages of granulation viz. nucleation, agglomeration, attrition and
breakage were taken for study individually or in combination to

Computationally less intensive as compared to conventional DEM.

formulate the kinetic model and the factors influencing the rates.
Population balance model with agglomerative rate term has been
employed to predict the particle size in a fluidized bed granulator
[317]. Granulation kinetics have been estimated using mass bal-
ance of granulated material considering the factors that lead to
decrease in the mass of granules viz., crushing and abrasion and
those that lead to its increase viz., coalescence and layering. The
PSD data was modelled along with RTD.

rate equation had three characteristic functions of discrete rate

function, agglomeration rate function and grinding rate function.
Using this rate model, the controlling factors could be easily iden-
providing comparable results.

coagulation rate expressions.

tified from various mechanisms [318]. Kinetics of tablet coating

Computationally expensive.

process in spouted bed were also investigated and it was found

that coating time had a critical role in maintaining the product
operational studies.

homogeneity apart from input (static bed height, particle geome-

experimentation.

try) and technological parameters (solution flow rate, gas flow rate,
intensity of particle motion) [319]. Granulation kinetics using a
up studies.

velocity.

high shear mixer was studied and it was found that coalescence
occurred only when the granules were saturated with the binder
and that mean granule size increased linearly with time. This indi-
cated that probability of coalescence was size dependent and
impeller torque was used to control the various phases of granula-
tion keeping the coalescence as a dominant phase [320]. The effect
Batch size 1 kg.

of powder type, free moisture content and deformation behaviour

on the kinetics of fluid bed granulation was studied by incorporat-
1.9 L, 4 L

Variable

Variable

ing coalescence kernel in PBM that considered the deformation

aspects. The moisture content in the range of 5–10% was found
to show no effect on the process which exhibited local plasticity
massing time, equipment size and particle
Batch Wurster FBG Equipment design and spray rate. Varying

Equipment dimensions, Binder properties,

caused due to the deposition of spray droplets onto the granules

Equipment dimensions, binder properties
Liquid to sold ratio, Impeller speed, Wet
Equipment dimensions, impeller speed.

with their subsequent absorption into the voids that forms a region
Equipment dimensions, and varying

of saturated voids [321]. Granule breakage that happens by various

Particle properties, impeller speed,

and flowrate, particle properties.

patterns viz., fracture, shattering, disintegration and total disinte-

spray rate and chopper speed.

Screw element configuration.

gration is a vital rate process that plays a critical role to achieve

granule homogeneity and strength (measured by tensile strength,
bending strength, dynamic yield strength and hardness) and hence
equipment design,

significantly affects process control and design. It was found that

impeller speed.

while granule breakage at process scale was influenced by the fac-

formulations.

Shaft speed

tors viz., binder viscosity, binder surface tension, contact angle

density.

between binder and the primary particle, primary particle size

and shape, binder content and addition method and intensity of
agitation, breakage at granule scale was influenced by bonding
forces in granules, forces due to immobile films, forces due to
Continous HSWG
Continous TSG

mobile liquid and solid bridges, forces due to attractive effects

Batch HSWG

Batch HSWG

Batch HSWG

Batch HSWG

Independent

between solid particles, forces due to interlocking between solid

Batch FBG

particles etc. [32]. Houslow et al., [322–324] have done elaborate

kinetic studies on fluidized bed melt granulation (FBMG) on vari-
ous aspects like understanding the influence of process variables
viz., binder spray rate, bed temperature, atomization pressure, flu-
PBM-Artificial Neural

idizing air velocity on the kinetics of FBMG; developing a model for

the net growth of granules and tracer studies to study breakage
And PDM-DEM

kinetics decoupled with granule size and age. The overall kinetics
PBM-DEM
PBM-DEM

PBM-DEM
PBM-CFD

PBM-CFD
Network

of FBMG process consists of steps like particle aggregation, binder

ROM

ROM

ROM

solidification and granule breakage. Tracer studies on granulation

kinetics in FBMG showed that granule breakage occurred at a much
slower rate than that of aggregation while tracer studies on
breakage-only kinetics revealed that breakage selection rate kinet-
ics was independent of granule size. Modelling studies were also
802
Table 7
Kinetic regimes.
Rate Processes Equations
Wetting and
tp ¼ e
1:35V 0
2 R
2=3
 c lcosh
Nucleation eff eff LV
Growth and kc ¼ bc expða St def Þ
Consolidation
Breakage and St def > St def
Attrition 6ð1eg Þ
 cLVd3;2
Y ¼ AR4:3 S½ eg cosh
ð1eg Þ2
þ 98 e2g  9plV P =16d3;2
conducted to estimate rate of granule growth in FBMG process by
including Equi-partition kinetic energy (EKE) kernel into PBM and
the results showed that aggregation rate increased with increase in
binder spray rate, increase in binder drop size, increase in bed tem-
perature if high viscosity binder was employed and decrease in air
velocity. The final GSD was found to get narrowed down with
increased bed temperature and air velocity. A novel at-line FBRM
technique (focused beam reflectance measurement) used to mea-
sure chord length distribution (CLD) was employed to study the
kinetics of FBG process and it was found binder spray rate was
the most influential parameter on the granule growth than the
other two factors considered viz., binder solution concentration
and intra- to extra-granular microcrystalline cellulose (MCC) ratio
for the formulation [210]. Studies were also done to understand
the influence of the initial poly-dispersity of particle size on
growth kinetics and mechanism of wet granulation of pharmaceu-
tical powders. It was found that when the particles had an initial
bimodal PSD, growth kinetics occurred in two stages, fast stage fol-
lowed by slow stage with former affected by amount of binder and
high probability of coalescence and the later affected by the water
content in the binder. For initial unimodal PSD, growth kinetics
exhibited only one slow stage as similar sized particles did not pro-
mote agglomeration. These results could be achieved by incorpo-
rating coalescence kernel that favors growth rate by collision
between small and large particles in PBM [325]. Modelling studies
employing EKE and SI (size independent) kernels (includes binder
volume fraction) with PBM were compared and it was found that
the later described the high shear wet granulation more effectively.
It was also found that aggregation constant was smaller in early
stages than in later stages of the granulation [313]. The effect of
operating conditions viz., impeller speed, binder flow rate and
the physic-chemical properties of binder viz., wettability and vis-
cosity on the granulation kinetics of MCC in high shear mixer
was studied and it was found that there existed an optimal impel-
ler speed below which uncontrollable aggregation and over wet-
ting occurs and above which granule breakage occurs. Increasing
the binder flow rate reduced the extension of non-growth regime
with no effect on granule mean size. The viscosity of the binder
solution was found to have only marginal influence on the granu-
lation process [22]. Recently a novel technique based on texture
analysis was successfully employed to study the kinetics of wet
granulation of MCC and this needs further development to be used
for rigorous applications [326].
Different dimensionless groups were found to influence differ-
ent rate processes of wet granulation. To have drop-controlled
nucleation and to avoid drop overlap thereby caking in a granula-
tor, ratio of penetration time (tp) to bed circulation time (tc) and
spray flux (w) need to be maintained very small respectively
[108]. As Stoke’s deformation number and viscous stokes number
P. Suresh et al. / Chemical Engineering Journal 328 (2017) 785–815
Descriptions Kinetic Parameters Limitations Ref.
Considers rate at which liquid flows sp ¼ < 0:1
tp
tc
Applicable for drop [249,329]
into the pores in the powder surface V_ controlled nucleation
ua ¼ 23Ad
_ < 0:2
under capillary action. d only (Ideal case)
For nearly elastic granules coated St v ;max < St  (non-inertial) Applicable for nearly [330]
with a layer of liquid. St v ;av  St  (inertial) elastic granules only
St v ;min > St  (Coating
regime)
Considers that granule will break if St* = 0.2 Oversimplified Model [168,331–333]
applied Kinetic energy during impact Stdef > 0.2 (granules are in
exceeds the energy required for breakage regime)
breakage. Both capillary and viscous
forces are taken into account in the
liquid bridges when strength of
granule is to be calculated.
vastly affect the growth and consolidation process and hence gran-
ule properties viz., density and PSD, it is vital to track their changes
to gain clarity in the granulation process [31,327].
qg U 2c
Stdef ¼ ð5Þ
2Y
The viscous Stokes number (Stv) which is the ratio of kinetic
energy to viscous work due to binding fluid occurring during gran-
ule/particle collisions denotes the likelihood of granule coales-
cence and growth. Low Stv favours granule coalescence and
growth which occurs for small granules, low relative collision
velocity u0 or granule density q, and high binder phase viscosity
m. Further, Stv visa vis its critical value helps to characterize the
type of growth phenomena i.e. non-inertial growth, inertial growth
and coating regime. In non-inertial growth, all the particle colli-
sions lead to coalescence and thus the growth was barely affected
by changes in process parameters which is contrary to inertial
growth. In the coating regime, the kinetic energy of the particles
was too high with very few collisions leading to coalescence and
hence granule growth occurs by successive layering [328].
7.1. Summary of kinetic studies
Though considerable research was reported on kinetics of phar-
maceutical wet granulation to understand the mechanisms,
regimes, rate limiting steps and influencing factors viz process,
material and formulation related, comprehensive and detailed
kinetic studies at a micro-level for the entire granulation process
are very limited. There have been reports on the kinetics of various
stages of granulation individually viz., granule growth, breakage,
coalescence, coating etc, the kinetic analysis that involves all the
stages simultaneously with rigorous regime mapping is very much
desired. Models that could be validated with experimental data
and mathematically less challenging need to be developed focusing
more on continuous granulation. This also requires the develop-
ment of sophisticated in line monitoring methods to measure var-
ious granulation phenomena as a function of time besides the
judicious use of the present tools. Effect of various process and
design parameters need to be factored in the models along with
scale of granulation.
Table 7 shows different kinetic regimes of wet granulation and
the relevant equations and parameters.
8. Scale up studies
Scale-up, defined as the transfer of the controlled process from
one scale to another was very vital for any technology as economic
viability could be achieved only by commercialization at an indus-
 P. Suresh et al. / Chemical Engineering Journal 328 (2017) 785–815
trial scale. Moreover, an operation like granulation is mostly
employed in industries viz., pharma, fertilizer, food, chemicals
etc. Process control and scale-up were very much related to one
another as effective process control by optimizing process and
design parameters at small scale acts as a basis for implementing
the process optimization at a larger scale. For a successful scale-
up, following rigorous criteria like geometric, kinematic and
dynamic similarities was very critical to get the maximum repro-
ducibility of the results achieved at lab or pilot scale. There have
been many studies reported on the scale-up of granulation. Con-
ventionally, classical dimensionless numbers like Power number,
Reynolds number and Froude number were employed to predict
the end point for scale-up in fixed bowl mixer granulator and
found that maintaining geometric similarity of the powder bed
was very much essential by keeping batch size in proportion to
shape of the mixer relative to the height of the parallel side.
Experimental scale-up studies on the basis of complete or par-
tial dimensional similarity have been pursued by researchers
extensively. In a study by Lister and Ennis [3] where scale-up of
lactose granulation was carried out from 25 L to 300 L high shear
mixer, there was a substantial increase in wa which could result
in a broader granule distribution at a large scale. Also a significant
rise in Stdef was calculated that could affect the maximum granule
size and its density. There is a need for more sophisticated quanti-
tative modelling so that actual granule size and density which
depend on nucleation and growth phenomena might be predicted
and scaled up with respect to Stdef. These studies justify the need to
look at the process at a micro-level along with ensuring dimen-
sional similarity. During scale up, it is also essential to hold the
impeller tip speed (to ensure kinematic similarity) and Froude
number (to ensure dynamic similarity) constant. During scale-up,
along with constant tip speed, similar rheology needs to be main-
tained. Several scale up studies [334–336] have been conducted
using constant Froude number and impeller tip speed using the fol-
lowing relation, where n is the scaling index, 0.5 for constant Fr
and 1 for constant tip speed.
NDn ¼ Constant
Tardos et al., [331] studied and concluded that the shear stress
remains constant when the scaling index was 0.8. This was most
commonly referred to as the ‘‘Constant Shear Stress rule”. Success-
ful scaling of their granulation model using constant shear stresses
had been carried out by Michael et al., [20]. However, it was gen-
erally agreed that there was no universally accepted rule for scale
up. Different scaling indices have been effective for different for-
mulations and granulators [336–339]. In pharmaceutical wet gran-
ulation by high shear granulators, power consumption was
monitored as it was related to liquid saturation and wet mass con-
sistency for effective process control and thereby scale-up. These
parameters of liquid saturation and wet mass consistency would
quantify the deformability and hence the PSD of the granules
formed [340]. Studies have shown that in scaling up a HSWG, the
amount of water (to achieve the same endpoint and drug perfor-
mance) in excess of the inflection point (percent of water added
at the point where the impeller load starts rising) for the granula-
tion at each scale rose by a constant percentage [341]. Studies by
Nakamura et al., [277] have shown that in order to attain dynamic
similarity, granulation time would have to be adjusted so that the
cumulative particle collision energy over the granulation time was
maintained constant at different scales of operation. Hence, apart
from the dimensional granulator scale up studies and the similarity
studies, the operating parameters on scale up too play an impor-
tant role as seen above.
Pandey et al., [342] reported that there were broadly two
approaches to such scale up, i.e. parametric approach and attribute
803
based approach. The attribute based approach works by focussing
on a targeted granule attribute and trying to keep it a constant by
varying other parameters and end point. This approach was mostly
used along with PAT tools such as FBRM, NIR, Raman spectroscopy
etc., on a given scaled up model, which helps in determining the
end point of process. Parameters such as power consumption were
used to monitor granulation process. Parametric approach on the
other hand, directly determines the scales up parameters using
scale up principles or factors and then product attributes were
tested. At this stage, if the target attributes didn’t match, the pro-
cess parameters were varied to match target attributes. Thus the
main difference was that, all the parameters were varied simulta-
neously according to scale up rules [342].
Power consumption has become a key monitoring parameter
during scale up and hence several relationships between power
consumption and the resulting agglomerate properties [343–345]
were developed, mainly the strength of the wet agglomerates
[346–349]. This mechanism of using power consumption as a mon-
itoring parameter was widely common in high shear mixers
[350,351]. Studies by Lindberg et al., [352] and Kristen et al.,
[353] have shown that the power consumption was related to
the saturation level and porosity of the granules. Other studies cor-
relating saturation level with average granule size for different
equipment and scale were available, thus making it easier to use
saturation level as a link between one machine and another
[354,355]. In an effort to refine this approach, a new term called
wet mass consistency, which describes the rheological properties
of wet mass, was used to replace saturation level in the above rela-
tionships [356,357]. It was recently identified in a study by Gab-
bott et al., [72] that specific granulation energy could be a useful
scaling parameter for batch wet granulation. However, it should
be noted that while following attribute based approach, PSD or
any other single parameter could not be treated adequate and con-
sider a combination of other parameters too besides determining
the exact end point of granulation [310,311,356–358].
In fluid bed granulation, moisture content in the bed that
played a vital role was monitored using NIR probes. The key
parameters in this granulation were droplet size, contact with
ð6Þ
the powder bed and humidity in the fluid bed which in turn
depends on temperature and humidity of the inlet air, the temper-
ature and amount of binder added and the extent of evaporation
observed [359]. For scaling up of FBG, it was highly important to
maintain hydrodynamic similarity as the particle growth was
related to the mixing and flow patterns of the powder in the bed.
Due to lower shear forces in fluidized beds, the liquid within the
agglomerate was less likely to be squeezed out and thus coales-
cence was highly limited [340]. In general, initial wetting of the
powder could be easily controlled, by effectively controlling the
spray droplet size and size distribution, taking into consideration
the phenomena such as surface renewal, clogging and wetting of
granular walls [333,360–363]. In a study conducted by Horio
et al., [364]. It was concluded that hydrodynamic similarity could
be achieved when factors viz., bed geometry (ratio of the bed
height to the particle diameter), distribution characteristics of
the particles, superficial velocities were maintained proportional
or constant.
In general, the parameters that need to be controlled during
scale-up in pharmaceutical wet granulation were grouped as five
categories viz., related to feed (not so important), machine (input
variables, spraying conditions, amount of solvent, mixing condi-
tions), drying (assumed constant in scale-up), granule attributes
(output variables like PSD, bulk density, porosity, residual moisture
content, strength, content uniformity etc) and post drying or
tablets attributes. For more complicated granulation processes
with large number of inter-related parameters, modeling and
numerical approaches by using fuzzy logic, ANN, PBMs etc based
804 P. Suresh et al. / Chemical Engineering Journal 328 (2017) 785–815
on experimental design were widely employed. Fluid bed granula-
tors employed in pharmaceutical applications were scaled up
empirically from small to medium and to large scales based on rel-
ative droplet size (depends on spray rate and nozzle settings) and
powder moisture content (depends on the balance between liquid
supply and evaporation) to achieve similar granule size as various
levels maintaining the air flow velocity and profiles constant. The
droplet size, estimated as the ratio of liquid mass to the quadratic
of air mass was found to have significant influence on granule size
if the moisture content was around 5% (w/w) and the granule size
was uncontrollable beyond the moisture content of 15% (w/w). The
droplet size was taken as the main criterion for scale up of fluid
bed granulation to large scale while experimental design and
regression models were employed for scale up from small to med-
ium scales [359]. There were reports using stokes number to iden-
tify the stability of the agglomerates and the shape and size of the
granules. It was found that at stokes number less than the critical
value, the agglomerates were stable and held strongly by the bin-
der and beyond the critical value, the agglomerates break down
while at the critical value, they were elongated in shape. This crit-
ical value of stokes number, thereby the shear forces generated
that depend on the wet mass and hence wetting were used for
scale-up studies to maintain kinematic similarity [365]. A compar-
ative study at pilot scale between single pot (blending, granulation
and drying conducted in a single apparatus) and multiphase high
shear wet granulation processes (mixer granulator followed by
fluid bed dryer) had demonstrated that regardless of formulation,
single pot granules were better in terms of PSD, packing, porosity,
flow properties, compressibility, and tablet cohesion but with more
sticky nature while tableting. The tablet characteristics viz., resid-
ual punch pressure, tensile strength, uniformity of mass and disso-
lution kinetics were found to be dependent on the nature of
formulation i.e. formulation properties and concentration of water
soluble substances present. Adjustment of volume of the granula-
tion liquid was necessary based on the formulation and the process
for effective switch between single pot and multiphase process at
industrial level [366]. It was also found from modeling studies val-
idated by experiments that steady states exist in a high shear
mixer granulator where the number of breaking agglomerates
was equal to the number of forming ones yielding a time indepen-
dent size distribution. To ensure steady state, binder liquid addi-
tion was maintained slow and wet massing time long so that
both these parameters had marginal influence on the final proper-
ties of the granules. This steady state so achieved at which granules
grew at equal rate was a function of only the amount of binder liq-
uid added at constant shear forces generated by the impeller (with
marginal role of chopper) and these findings had a very important
bearing for a highly simplified and accurate scale-up under con-
trolled process conditions. Identification of impeller speed to main-
tain constant shear for geometrically dissimilar systems at
different scales remains a challenge in this method [20]. Three
scale-up rules of constant tip speed, constant Froude number and
constant shear stress were compared for scale-up studies at 1 L,
5 L and 50 L cyclo-mix high shear granulator on calcium carbonate
with PEG as binder. It was found that using the first condition of
constant tip speed, granules of almost similar strength were pro-
duced but with the condition of constant shear, 1l gave weaker
granules than those from 5 L and 50 L vessels. PEPT studies also
showed that macro-flow fields and hence the final structure of
agglomerates were different under constant shear conditions and
the smallest vessel produced granules with higher elongation fac-
tor and lower packing fraction. Studies also revealed that direct
scale-up by a factor of 50 could be easily achieved with geometri-
cally similar vessels at a constant water addition time and tip
speed by assuming a linear relationship between the impeller
power inflection point (percent of water added where impeller
load starts rising) and the Froude number. Hence impeller power
in combination with proper impeller blade design would accelerate
and simplify the scale-up in pharmaceutical wet granulation.
Impeller power and water addition were found to be critical con-
trol parameters to ensure product quality and they were strongly
related as more water or more power were needed to reach same
granulation end point and drug product performance [334,341].
Binder less fluidized bed granulator working on a hygroscopic
and poor flowing pharmaceutical powder (dry powder inhalers)
could also be scaled up to pilot level with improved product attri-
butes viz., improved flow properties, moisture content, desired
particle morphology, PSD by incorporating a drying unit in a fluid
bed operating with a wet air [367]. Scale-up studies in a high shear
mixer granulator have been done employing correlations of differ-
ent dimensionless numbers viz., power number, Froude number,
Reynolds number, relative swept volume, spray flux and the wet-
ted powder properties. Constant tip speed (kinematic similarity)
and constant Froude number (dynamic similarity) besides geomet-
ric similarity were the most common empirical rules used in scale-
up. Simulations studies were done using 3D-DEM to develop the
scale up protocol for a high shear mixer granulator by maintaining
kinematic and dynamic similarities keeping impeller tip speed
constant and by using optimal granulation time so as to maintain
internal particle flow and cumulative particle collision energy
respectively [277]. Robustness and parametric sensitivity studies
in a high shear pharmaceutical wet granulation at various scales
indicated a need of in-depth study of the impact of process param-
eters and scale on the microstructure of granules as the macro-
properties like bulk density, PSD alone could not explain dissolu-
tion trends. These studies were essential in the light of QbD con-
cept [85]. Studies though limited were reported on the
development of effective feedback control strategies useful at
industrial level like single and multiple feedback (cascade) loop
controllers to suppress or eliminate the disturbances and maintain
the desired operational conditions in the granulation process and it
was also found that cascade controller were more effective [368].
Effective process control and optimization demands effective mon-
itoring and end point detection methods as granule growth is
highly complex and sensitive to raw materials, process conditions
and the equipment.
8.1. Summary of Scale-up
Like any other technology, wet granulation also needs to be
scaled up from lab to pilot to industrial scale by using the concept
of dimensional analysis viz., maintaining geometric, kinematic and
dynamic similarities. On a macro scale empirical techniques have
been developed in high shear mixers while computing techniques
were being developed for more complicated fluid bed granulation.
With the advent of regime mapping and various models like PBM,
fundamental knowledge of the process is largely available to sup-
port macro scale monitoring approaches. More rigorous studies are
needed on the effect of scale up on various granule and tablet attri-
butes including the structure as only few properties like strength,
PSD were reported. Similarly the effect of feed material, process
parameters, formulation attributes, granulator design and tablet
characteristics on the scale up efficiency need to be focused. This
again requires the usage of novel process monitoring tools applica-
ble to various scales and work at equal accuracy. The criteria for
scale up for various granulators like power consumption, moisture
content, tip speed, shear stress, Froude number etc need to be reas-
sessed to find the better, simple and accurate criteria. More
advanced feedback control strategies like multiple and cascade
 P. Suresh et al. / Chemical Engineering Journal 328 (2017) 785–815
Table 8
Scale-up of batch granulation technologies.
Granulation Technology Scale-up feasibility
High/low shear mixers
Very difficult as powder flow pat-
terns vary with scale

Nucleation, growth and attrition
rates differ on different scales
Fluidized bed granulator
Easier compared to a high shear
mixer
controllers need to be implemented for effective process control
and scale up.
Table 8 consolidates all these discussions and presents the
equations which govern scale up for HSWGs and FBG.
9. Process control
Effective process control plays a pivotal role in achieving the
desired attributes of granules and tablets. It also facilitates efficient
scale up but requires the sophisticated feedback-control strategies
and in-line or off-line monitoring of the process. Large number of
variables, desired attributes and granulators that could work in
batch or continuous modes make the process control in granula-
tion even more challenging. Hence granulation has been treated
as an art than a science [370]. Though in recent times, there have
been several techniques such as in-line characterization tools and
mathematical models to help simulate the entire process, these
techniques too were limited by either a lack of proper process
knowledge or limited scope in accurately identifying changes in
the attributes during the process. However, there has been some
success in this regard, thanks to the advent of PAT and the empha-
sis on QbD by FDA, researchers have been able to achieve process
control with some level of success.
The first step in ensuring process control was identifying the
relationships between product attributes and the various process
variables. Hence, CQAs viz., PSD, porosity, dissolution characteris-
tics, strength etc for the granules need to be identified first as it
would help facilitate easy selection of the type and scale of equip-
ment to be used. Then a careful analysis of the key variables affect-
ing each CQA would help in selecting the suitable materials,
equipment design and process parameters. This approach however
was not always feasible due to the lack of basic knowledge on the
functioning of various granulator systems under various conditions
and the results also not being universal to all formulations. Thus in
such cases, process control need to be achieved using modelling
studies and or through integrated use of characterization
techniques. This approach relies on tracking the changes in granule
attributes with time and modifying process parameters and end-
point accordingly. Some of the simpler end point determination
techniques in literature involve monitoring of power consumption
805
Key Scale-up parameters Ref
1) Geometric similarity [331,334–336,369]

DDc ; Hm should be constant

s hape, positioning of impeller and chopper
should be same on scale-up
2) Powder pattern similarity

Froude No. should be constant

Fill ratio should be constant
3) Constant impeller speeds
4) Constant swept volume
5) Constant shear rateprovided the bowl and impeller
geometries are th/e same
1) Maintaining hydrodynamic similarity [333,363,364,369]
2) Following parameters need to be kept constant
d uq

Rep ¼ p l G

qs =qG
0:5

Fr p ¼ u=ðgdp Þ

L=dp (geometric similarity of distributor, bed and
particle)

Scaling rules for ambient air and similar kind of
particlespffiffiffiffiffi
u2  umf2 ¼ m (u1  umf1 Þ
pffiffiffiffiffi
umf2 ¼ mumf1
m ¼ L2 =L1
(in HSWGs). This was based on the linear dependency found
between the mean granule size and power consumption. However,
this dependency with power consumption was limited to impeller
design, speed, liquid addition rate and type of binders [371,372].
On-line measurement based control schemes are also highly pop-
ular. Recently, Narang et al., [373] had reported a study based on
the application of FRBM as an inline characterization tool to deter-
mine appropriate end point for HSWG. Similarly, studies involving
other characterization tools such as NIR, AE and DSC have also been
reported for various formulations and granulators [374–378]. MPC
studies were also used quite commonly in achieving process con-
trol in wet granulation [379–382].
MPC scheme consists of simultaneous determination of manip-
ulative variables and uncertain parameters [257]. Pottmann et al.,
[382] reported a MPC control structure for granulation validated
by experimentation. Sanders et al., [380] had developed a linear
MPC applicable to non-linear process granulation, and showed that
for stable control of PSD, MPC setup was much better than generic
PID controls. However, more often in these studies the control
parameter of interest has been the particle size. Also limited stud-
ies have been reported for control systems of an integrated contin-
uous wet granulation process [383]. Singh et al., [384] reported a
closed loop feedback control for continuous processing using a
TSG. Alternatively, optimization and process control of wet granu-
lation could also be performed using fuzzy logic modelling and
artificial neural net-working [385]. A study by Petrovic et al.,
[386] showed that process control based on nonlinear methods
such as neural networks were better in terms of generalization
and prediction as compared to the conventional regression analy-
sis. However, the drawback of using data mining techniques such
as artificial neural networks for process control was their require-
ment of data, which calls for extensive experimentation. Process
control could thus be achieved by carefully employing any of the
above mentioned techniques. Hence there is a need to develop rig-
orous process control techniques using effective feedback control
strategies, precise and less time consuming mathematical models
assisted by sophisticated in-line monitoring methods that measure
the attributes of granules and tablets dynamically. Table 9 below
summarizes the process parameters and their qualitative and
quantitative correlations with various granule attributes for differ-
ent granulators.
Table 9

806
Overview of various correlations between processing parameters and granulated product attributes.

S.No Granulator Mode of Process/ Effect on Granule Attributes Correlations Applications Challenges/Comments Ref.
Operation Design
Parameter
1. Low and High Batch and Impeller Increased impeller speed Lower Impeller speed is used for Impeller speed has a constraint in the [46,59–62,387]
shear mixer Continuous Speed results in compact, narrow heat sensitive APIs. Whereas Higher form of temperature which affects the
Granulator PSD, high strength particles, speeds may be used for highly whole process, especially when we
however at the cost of cohesive materials. have heat sensitive API.
porosity and dissolution
characteristics.
Fill Ratio Higher fill ratio leads to Typically fill ratios: 50– Fines affect final tableting Overloading above this value leads to [52,53]
increased amount of fines 70% for efficient properties due to non-uniformity. inadequate mixing and granulation,
being formed. granulation. and increased load on impeller.
Impeller Higher inclinations give Porosity and dissolution are directly This is due to increased compaction [56]
blade angle granules of low porosity, affected influencing tablet that the particles are subjected to.
increased strength and performance.
narrow PSD.

P. Suresh et al. / Chemical Engineering Journal 328 (2017) 785–815

L/S ratio Increasing L/S ratio leads to
increased average particle
size and decrease in porosity.
Chopper At appropriate impeller
presence and speeds (and chopper speeds),
speed the chopper helps in
producing fine granules of
uniform PSD and avoids
caking.
Binder Average particle size is
Viscosity directly dependent on
impeller speed for higher
viscosity binder while the
opposite is true for low
viscosity binder.
2. Fluid bed Batch and Atomizer The process efficiency was
Granulator Continuous position seen to decrease with
increase in atomizer level
above fixed bed.
Fluidizing air Higher flow rate: Smaller
velocity friable granules.
Lower flow rate: Larger and
denser granules.
Fluidizing air Higher temperatures favour
temperature drying and hence, small
average size particles are
formed.
Inlet air Increased Moisture content is
Humidity catered, leading to more
growth or increased PSD.
3. Twin Screw Continuous Powder Feed Increased Powder feed rate
Granulator Rate (PFR) qualitatively leads to
increased sphericity,
compaction and strength of
granules.
L
S / RT Porosity and dissolution are directly
affected influencing tablet
performance.
Increases efficiency of granulation
and gives uniform API loading.
Optimal position: when Helps get optimal granulation as a
the tip of the nozzle balance between growth phase and
coincided with the drying.
surface of the packed
bed, (submerged when
fluidized).
Affects directly the residence time
and thus final particle size.
Influences particle size.
Affects both the wetting and drying
stage, directly influencing the
particle size to a significant extent.
PFR / RT
1 Sphericity has a direct effect on
PFR / s flow-ability of particles, while
strength has a direct effect on
dissolution.
[64,388]
At low impeller speed the chopper has [63,389–391]
no significant effect granule attributes,
and at high impeller speeds due to
caking at the boundaries the chopper
does not influence the process much.
This correlation is however not [66]
necessarily true as more often other
parameters masks its effect.
This is because both wall wetting and [392,393]
spray drying is favoured with increase
in atomizer height.
This is due to increased probability of [392]
contact between wetted articles at
lower flow rates. Higher flowrates
could results in entrainment.
There exists some constraints on the [102]
temperature, especially if we are
dealing with heat sensitive API nature.
The same result is also seen in lower [102]
fluidization air temperature and dilute
binder solution due to increased
moisture leading to more liquid bridges
being formed.
There is an interplay between strength [387,394,395]
and PSD as RT tends to favour narrow
PSD which however leads to lower
torque and thus decreased strength and
large porous particles.
 P. Suresh et al. / Chemical Engineering Journal 328 (2017) 785–815 807

10. Conclusions

Wet granulation focussing on pharmaceutical applications has

[128,129,396]
been reviewed comprehensively with ref to various aspects like
[387,394]

[387,394]

[128,129] granulation technologies, characterization tools, modelling and

simulation studies, kinetics, process control and scale up. It can
be understood that granulation process is highly complex in terms
particle size increases as we have given
Though the PSD is narrow, the average

of large number of variables affecting the process and the stringent

granulating liquid. This also however

affected significantly by screw speed

This is due to increased intensity of

more RT for the particles to adhere.

and large number of attributes desired of the product. Though

leads to irregular shaped particles.

Flow-ability and strength are not

there has been considerable research efforts focussed on the above

pharmaceutical point of view.

said aspects over the past few decades, few challenges as given
However constraints for the

mixing of the powders with

temperature exist from a

under need to be addressed.

More studies on continuous granulation processes in terms of

the granulator systems, process control and scale up are needed
as pharmaceutical granulation hitherto run in batch mode is
turning towards continuous for enhanced efficiency and
though.

productivity.

Focus should be now diverted to tap the potential of the uncon-
ventional granulation methods like foam, melt, dry and steam
distribution and increased strength.
The friability (measure of strength)
The solubility of the powder in the

granulation and thus uniform API

granulating liquid increases with

granulations as not many studies have been reported.

temperature, leading to efficient
sphericity influences dissolution

increases along with a narrower

and flow-ability of the particles.

As process control, scale up, kinetics, equipment design depend

Shape of the particles affect
dissolution of the particles.
Narrow PSD, strength and

on the precise and continuous measurement of granule and

tablet attributes, effective but simple in-line monitoring meth-
ods need to be developed that suit most of the systems.

Mathematical modelling studies though have evolved a great
deal from PBM to the coupled models, there is still a great scope
to develop rigorous but simple models that take care of all the
complexities in the granulation process.
PSD.

Comprehensive kinetic studies that involve all the granulation

steps like wetting and nucleation; agglomeration and growth
and attrition and breakage need to be done to get a comprehen-
sive understanding of the process, mechanism and controlling
Screw speed / RT
1

factors.
Screw speed / 1s

No:kn:el: / RT

Rigorous methodologies for scale up from lab to industrial

levels need to be developed based on different criteria for differ-
L=S / RT
L=S / s

ent granulators apart from the conventional ones like power

consumption, tip speed, stress etc using effective modelling
techniques and characterization tools.
Increasing Barrel temperature
increased sphericity, reduced

Correlations between various input factors viz., material, pro-

Increased L/S ratio leads to

decreases average particle

increased average particle

Decreases fines, increases

size and lead to irregular

cess, equipment and output attributes viz., granule and tablet

fines (narrow PSD) and

increased strength and

Increased Screw speed

strength and increases

average particle size.
lead decreased fines,

need to be developed for various granulation methods which

would facilitate easy process control and scale up.
shaped particles.

Though kinetic studies have been reported on granulation pro-

cess, more studies are required on tableting too which is impor-
strength.

tant for pharmaceutical industry.

size.

As binders play a critical role in wet granulation process, contin-

uous efforts need to be done in identifying cost effective and
efficient binders that work well even in small amounts.
Temperature
Screw Speed

kneading
elements
L/S ratio

Barrel

No. of

Acknowledgements

The authors would like to express their gratitude to the man-

agement of BITS Pilani, Hyderabad campus, for funding and other
Note: RT: Residence Time, s: Torque.

contributions towards the research work.

References

[1] B.J. Ennis, J.D. Litster, Perry‘s Chemical Engineers‘ Handbook, McGraw Hill,
New York, 1997.
[2] A. Kumar, K.V. Gernaey, T. De Beer, I. Nopens, Model-based analysis of high
shear wet granulation from batch to continuous processes in pharmaceutical
production – a critical review, Eur. J. Pharm. Biopharm. 85 (2013) 814–832,
http://dx.doi.org/10.1016/j.ejpb.2013.09.013.
[3] J.D. Litster, B.J. Ennis, The Science and Engineering of Granulation Processes,
Springer, 2004.
808 P. Suresh et al. / Chemical Engineering Journal 328 (2017) 785–815
[4] R.M. Dhenge, J.J. Cartwright, M.J. Hounslow, A.D. Salman, Twin screw
granulation: Steps in granule growth, Int. J. Pharm. 438 (2012) 20–32,
http://dx.doi.org/10.1016/j.ijpharm.2012.08.049.
[5] B.J. Ennis, Theory of granulation: An engineering perspective, in: D. Parikh
(Ed.), Handb. Pharm. Granulation Technol., third ed., Informa Healthcare,
2005, pp. 6–58, http://dx.doi.org/10.1201/9780849354953.
[6] P. Soyeux, A. Delacourte, B. Delie, P. Lefevre, B. Boniface, Influence and
optimisation of operating parameters with a new binder in wet granulation. I:
use in powder form, Eur. J. Pharm. Biopharm. 46 (1998) 95–103, http://dx.doi.
org/10.1016/S0939-6411(97)00162-8.
[7] D. Parikh (Ed.), Handbook of Pharmaceutical Granulation Technology, third
ed., Informa Healthcare, New York, 2010, http://dx.doi.org/10.1201/
9780849354953.
[8] J. Quodbach, P. Kleinebudde, A critical review on tablet disintegration, Pharm.
Dev. Technol. (2015) 1–12, http://dx.doi.org/10.3109/
10837450.2015.1045618.
[9] B.J. Ennis, Agglomeration and size enlargement session summary paper,
Powder Technol. 88 (1996) 203–225, http://dx.doi.org/10.1016/S0032-5910
(96)03124-5.
[10] A. Burggraeve, T. Monteyne, C. Vervaet, J.P. Remon, T. De Beer, Process
analytical tools for monitoring, understanding, and control of pharmaceutical
fluidized bed granulation: a review, Eur. J. Pharm. Biopharm. 83 (2013) 2–15,
http://dx.doi.org/10.1016/j.ejpb.2012.09.008.
[11] P. Rajniak, F. Stepanek, K. Dhanasekharan, R. Fan, C. Mancinelli, R.T. Chern, A
combined experimental and computational study of wet granulation in a
Wurster fluid bed granulator, Powder Technol. 189 (2009) 190–201, http://
dx.doi.org/10.1016/j.powtec.2008.04.027.
[12] T.H. Nguyen, D.A.V. Morton, K.P. Hapgood, Application of the unified
compaction curve to link wet granulation and tablet compaction behaviour,
Powder Technol. 240 (2013) 103–115, http://dx.doi.org/10.1016/j.
powtec.2012.07.001.
[13] L. Shi, Y. Feng, C.C. Sun, Origin of profound changes in powder properties
during wetting and nucleation stages of high-shear wet granulation of
microcrystalline cellulose, Powder Technol. 208 (2011) 663–668, http://dx.
doi.org/10.1016/j.powtec.2011.01.006.
[14] S. Oka, H. Emady, O. Kašpar, V. Tokárová, F. Muzzio, F. Štěpánek, R.
Ramachandran, The effects of improper mixing and preferential wetting of
active and excipient ingredients on content uniformity in high shear wet
granulation, Powder Technol. 278 (2015) 266–277, http://dx.doi.org/10.1016/
j.powtec.2015.03.018.
[15] E.M. Hansuld, L. Briens, A review of monitoring methods for pharmaceutical
wet granulation, Int. J. Pharm. 472 (2014) 192–201, http://dx.doi.org/
10.1016/j.ijpharm.2014.06.027.
[16] M.A. Järvinen, M. Paavola, S. Poutiainen, P. Itkonen, V. Pasanen, K. Uljas, K.
Leiviskä, M. Juuti, J. Ketolainen, K. Järvinen, Comparison of a continuous ring
layer wet granulation process with batch high shear and fluidized bed
granulation processes, Powder Technol. 275 (2015) 113–120, http://dx.doi.
org/10.1016/j.powtec.2015.01.071.
[17] L. Shi, Y. Feng, C.C. Sun, Initial moisture content in raw material can
profoundly influence high shear wet granulation process, Int. J. Pharm. 416
(2011) 43–48, http://dx.doi.org/10.1016/j.ijpharm.2011.05.080.
[18] D. Newitt, J. Conway-Jones, A contribution to the theory and practice of
granulation, Trans. Inst. Chem. Eng. 36 (1958) 422–441.
[19] C.E. Capes, P. Danckwetz, Granule formation by the agglomeration of damp
powders: Part 1. The mechanism of granule growth, Trans. Inst. Chem. Eng.
43 (1965) 116–124.
[20] J.N. Michaels, L. Farber, G.S. Wong, K. Hapgood, S.J. Heidel, J. Farabaugh, J.-H.
Chou, G.I. Tardos, Steady states in granulation of pharmaceutical powders
with application to scale-up, Powder Technol. 189 (2009) 295–303, http://dx.
doi.org/10.1016/j.powtec.2008.04.028.
[21] S.M. Iveson, J.D. Litster, K. Hapgood, B.J. Ennis, Nucleation, growth and
breakage phenomena in agitated wet granulation processes: a review,
Powder Technol. 117 (2001) 3–39, http://dx.doi.org/10.1016/S0032-5910
(01)00313-8.
[22] M. Benali, V. Gerbaud, M. Hemati, Effect of operating conditions and physico-
chemical properties on the wet granulation kinetics in high shear mixer,
Powder Technol. 190 (2009) 160–169, http://dx.doi.org/10.1016/j.
powtec.2008.04.082.
[23] B.J. Ennis, J. Li, Gabriel I. Tardos, P. Robert, The influence of viscosity on the
strength of an axially strained pendular liquid bridge, Chem. Eng. Sci. 45
(1990) 3071–3088, http://dx.doi.org/10.1016/0009-2509(90)80054-I.
[24] B.J. Ennis, G. Tardos, R. Pfeffer, A microlevel-based characterization of
granulation phenomena, Powder Technol. 65 (1991) 257–272, http://dx.doi.
org/10.1016/0032-5910(91)80189-P.
[25] M. Aulton, M. Banks, Influence of the hydrophobicity of the powder mix on
fluidised bed granulation, in: Int. Conf. Powder Technol. Pharm., BAsel,
Switzerland, 1979.
[26] T. Schæfer, C. Mathiesen, Melt pelletization in a high shear mixer. IX. Effects
of binder particle size, Int. J. Pharm. 139 (1996) 139–148, http://dx.doi.org/
10.1016/0378-5173(96)04548-6.
[27] T. Schæfer, C. Mathiesen, Melt pelletization in a high shear mixer. VIII. Effects
of binder viscosity, Int. J. Pharm. 139 (1996) 125–138, http://dx.doi.org/
10.1016/0378-5173(96)04549-8.
[28] S.T. Keningley, P.C. Knight, A.D. Marson, An investigation into the effects of
binder viscosity on agglomeration behaviour, Powder Technol. 91 (1997) 95–
103, http://dx.doi.org/10.1016/S0032-5910(96)03230-5.
[29] S.M. Iveson, J.D. Litster, B.J. Ennis, Fundamental studies of granule
consolidation Part 1: Effects of binder content and binder viscosity, Powder
Technol. 88 (1996) 15–20, http://dx.doi.org/10.1016/0032-5910(96)03096-3.
[30] L. Vialatte, Me’canismes de granulation. Application a‘ la granulation par
agitation me’canique, Universite’ de Technologie deCompie‘gne, Fevrier,
1998.
[31] K. van den Dries, O.M. de Vegt, V. Girard, H. Vromans, Granule breakage
phenomena in a high shear mixer; influence of process and formulation
variables and consequences on granule homogeneity, Powder Technol. 133
(2003) 228–236, http://dx.doi.org/10.1016/S0032-5910(03)00106-2.
[32] G.K. Reynolds, J.S. Fu, Y.S. Cheong, M.J. Hounslow, A.D. Salman, Breakage in
granulation: a review, Chem. Eng. Sci. 60 (2005) 3969–3992, http://dx.doi.
org/10.1016/j.ces.2005.02.029.
[33] J.B. Wade, G.P. Martin, D.F. Long, Controlling granule size through breakage in
a novel reverse-phase wet granulation process; the effect of impeller speed
and binder liquid viscosity, Int. J. Pharm. 478 (2015) 439–446, http://dx.doi.
org/10.1016/j.ijpharm.2014.11.067.
[34] D.A. Pohlman, J.D. Litster, Coalescence model for induction growth behavior
in high shear granulation, Powder Technol. 270 (2015) 435–444, http://dx.
doi.org/10.1016/j.powtec.2014.07.016.
[35] R. Rowe, G. Sadeghnejad, The rheology of microcrystalline cellulose powder/
water mixes—measurement using a mixer torque rheometer, Int. J. Pharm. 38
(1987) 227–229, http://dx.doi.org/10.1016/0378-5173(87)90118-9.
[36] W.F. Sakr, M.A. Ibrahim, F.K. Alanazi, A.A. Sakr, Upgrading wet granulation
monitoring from hand squeeze test to mixing torque rheometry, Saudi
Pharm. J. 20 (2012) 9–19, http://dx.doi.org/10.1016/j.jsps.2011.04.007.
[37] B. Hancock, Material Interactions and Surface Phenomena in Size
Enlargement Processes : An Evaluation of the Interactions Occuring During
the Wet Granulation of Real and Model Pharmaceutical Systems, University
of Bradford, 1991.
[38] B.C. Hancock, P. York, R.C. Rowe, An assessment of substrate-binder
interactions in model wet masses. 1: Mixer torque rheometry, Int. J. Pharm.
102 (1994) 167–176, http://dx.doi.org/10.1016/0378-5173(94)90052-3.
[39] M. Landin, The effect of batch size on scale-up of a pharmaceutical
granulation in a fixed bowl mixer granulator, Int. J. Pharm. 134 (1996)
243–246, http://dx.doi.org/10.1016/0378-5173(96)04461-4.
[40] G.I. Tardos, R. Gupta, Forces generated in solidifying liquid bridges between
two small particles, Powder Technol. 87 (1996) 175–180, http://dx.doi.org/
10.1016/0032-5910(95)03074-3.
[41] B.C. Hancock, P. York, R.C. Rowe, Characterization of wet masses using a
mixer torque rheometer: 2. Mixing kinetics, Int. J. Pharm. 83 (1992) 147–153,
http://dx.doi.org/10.1016/0378-5173(82)90017-5.
[42] S.D. Schaber, D.I. Gerogiorgis, R. Ramachandran, J.M.B. Evans, P.I. Barton, B.L.
Trout, Economic Analysis of Integrated Continuous and Batch Pharmaceutical
Manufacturing: A Case Study, Ind. Eng. Chem. Res. 50 (2011) 10083–10092,
http://dx.doi.org/10.1021/ie2006752.
[43] R. Gokhale, N.R. Trivedi, Handbook in Pharmacuetical Granulation, third ed.,
Drugs and Pharmaceutical Sciences, 2010.
[44] P. Knight, J.P. Seville, A. Wellm, T. Instone, Prediction of impeller torque in
high shear powder mixers, Chem. Eng. Sci. 56 (2001) 4457–4471, http://dx.
doi.org/10.1016/S0009-2509(01)00114-2.
[45] L. Cai, L. Farber, D. Zhang, F. Li, J. Farabaugh, A new methodology for high drug
loading wet granulation formulation development, Int. J. Pharm. 441 (2013)
790–800, http://dx.doi.org/10.1016/j.ijpharm.2012.09.052.
[46] D. Oulahna, F. Cordier, L. Galet, J. Dodds, Wet granulation: the effect of shear
on granule properties, Powder Technol. 130 (2003) 238–246, http://dx.doi.
org/10.1016/S0032-5910(02)00272-3.
[47] M. Cavinato, E. Andreato, M. Bresciani, I. Pignatone, G. Bellazzi, E.
Franceschinis, N. Realdon, P. Canu, A.C. Santomaso, Combining formulation
and process aspects for optimizing the high-shear wet granulation of
common drugs, Int. J. Pharm. 416 (2011) 229–241, http://dx.doi.org/
10.1016/j.ijpharm.2011.06.051.
[48] M. Börner, M. Michaelis, E. Siegmann, C. Radeke, U. Schmidt, Impact of
impeller design on high-shear wet granulation, Powder Technol. 295 (2016)
261–271, http://dx.doi.org/10.1016/j.powtec.2016.03.023.
[49] A. Kaćunić, M. Akrap, N. Kuzmanić, Effect of impeller type and position in a batch
cooling crystallizer on the growth of borax decahydrate crystals, Chem. Eng. Res.
Des. 91 (2013) 274–285, http://dx.doi.org/10.1016/j.cherd.2012.07.010.
[50] T. Kumaresan, J.B. Joshi, Effect of impeller design on the flow pattern and
mixing in stirred tanks, Chem. Eng. J. 115 (2006) 173–193, http://dx.doi.org/
10.1016/j.cej.2005.10.002.
[51] T. Schaefer, P. Holm, H. Kristensen, Comparison between granule growth in a
horizontal and a vertical high speed mixer. I. Granulation of dicalcium
phosphate, Arch. Pharm, Chem. Sci. 14 (1986) 1–16.
[52] T.K. Bock, U. Kraas, Experience with the Diosna mini-granulator and
assessment of process scalability, Eur. J. Pharm. Biopharm. 52 (2001) 297–
303, http://dx.doi.org/10.1016/S0939-6411(01)00197-7.
[53] D. Verkoeijen, G.A. Pouw, G.M.H. Meesters, B. Scarlett, Population balances for
particulate processes—a volume approach, Chem. Eng. Sci. 57 (2002) 2287–
2303, http://dx.doi.org/10.1016/S0009-2509(02)00118-5.
[54] A.M. Bouwman, M.R. Visser, A.C. Eissens, J.A. Wesselingh, H.W. Frijlink, The
effect of vessel material on granules produced in a high-shear mixer, Eur. J.
Pharm. Sci. 23 (2004) 169–179, http://dx.doi.org/10.1016/j.ejps.2004.07.008.
[55] P. Holm, Effect of impeller and chopper design on granulation in a high speed
mixer, Drug Dev. Ind. Pharm. 13 (1987) 1675–1701, http://dx.doi.org/
10.3109/03639048709068687.
 P. Suresh et al. / Chemical Engineering Journal 328 (2017) 785–815
[56] N. Rahmanian, A. Naji, M. Ghadiri, Effects of process parameters on granules
properties produced in a high shear granulator, Chem. Eng. Res. Des. 89
(2011) 512–518, http://dx.doi.org/10.1016/j.cherd.2010.10.021.
[57] C. Mangwandi, M.J. Adams, M.J. Hounslow, A.D. Salman, Effect of impeller
speed on mechanical and dissolution properties of high-shear granules,
Chem. Eng. J. 164 (2010) 305–315, http://dx.doi.org/10.1016/j.
cej.2010.05.039.
[58] V. Boonkanokwong, B. Remy, J.G. Khinast, B.J. Glasser, The effect of the
number of impeller blades on granular flow in a bladed mixer, Powder
Technol. 302 (2016) 333–349, http://dx.doi.org/10.1016/j.
powtec.2016.08.064.
[59] C.C. Kwan, Y. Ding, R.A. Williams, M. Ghadiri, Effects of operating parameters
of high shear granulator on the evolved properties and structure of calcium
carbonate granules, in: Part. Syst. Anal., 2005.
[60] M.B. Mackaplow, L.A. Rosen, J.N. Michaels, Effect of primary particle size on
granule growth and endpoint determination in high-shear wet granulation,
Powder Technol. 108 (2000) 32–45, http://dx.doi.org/10.1016/S0032-5910
(99)00203-X.
[61] I. Ohno, S. Hasegawa, S. Yada, A. Kusai, K. Moribe, K. Yamamoto, Importance
of evaluating the consolidation of granules manufactured by high shear
mixer, Int. J. Pharm. 338 (2007) 79–86, http://dx.doi.org/10.1016/j.
ijpharm.2007.01.030.
[62] I.P. Gabbott, Designer Granules: Beating the trade off between Granule
Strength and Dissolution Time, The University of Sheffield, 2007.
[63] F. Hoornaert, P.A.L. Wauters, G.M.H. Meesters, S.E. Pratsinis, B. Scarlett,
Agglomeration behaviour of powders in a Lödige mixer granulator, Powder
Technol. 96 (1998) 116–128, http://dx.doi.org/10.1016/S0032-5910(97)
03364-0.
[64] S. Oka, O. Kašpar, V. Tokárová, K. Sowrirajan, H. Wu, M. Khan, F. Muzzio, F.
Štěpánek, R. Ramachandran, A quantitative study of the effect of
process parameters on key granule characteristics in a high shear wet
granulation process involving a two component pharmaceutical blend, Adv.
Powder Technol. 26 (2015) 315–322, http://dx.doi.org/10.1016/j.
apt.2014.10.012.
[65] L. Shi, Y. Feng, C.C. Sun, Massing in high shear wet granulation can
simultaneously improve powder flow and deteriorate powder compaction:
a double-edged sword, Eur. J. Pharm. Sci. 43 (2011) 50–56, http://dx.doi.org/
10.1016/j.ejps.2011.03.009.
[66] P. Knight, A. Johansen, H. Kristensen, T. Schæfer, J.P. Seville, An investigation
of the effects on agglomeration of changing the speed of a mechanical mixer,
Powder Technol. 110 (2000) 204–209, http://dx.doi.org/10.1016/S0032-5910
(99)00259-4.
[67] M. Ritala, P. Holm, T. Schaefer, H.G. Kristensen, Influence of liquid bonding
strength on power consumption during granulation in a high shear mixer,
Drug Dev. Ind. Pharm. 14 (1988) 1041–1060, http://dx.doi.org/10.3109/
03639048809151919.
[68] E. Rondet, M. Delalonde, T. Ruiz, J.P. Desfours, Fractal formation description of
agglomeration in low shear mixer, Chem. Eng. J. 164 (2010) 376–382, http://
dx.doi.org/10.1016/j.cej.2010.03.069.
[69] M.M. Saad, A. Barkouti, E. Rondet, T. Ruiz, B. Cuq, Study of agglomeration
mechanisms of food powders: application to durum wheat semolina, Powder
Technol. 208 (2011) 399–408, http://dx.doi.org/10.1016/j.
powtec.2010.08.035.
[70] A. Barkouti, E. Rondet, M. Delalonde, T. Ruiz, Influence of physicochemical
binder properties on agglomeration of wheat powder in couscous grain, J.
Food Eng. 111 (2012) 234–240, http://dx.doi.org/10.1016/j.
jfoodeng.2012.02.028.
[71] M. Fonteyne, H. Wickström, E. Peeters, J. Vercruysse, H. Ehlers, B.-H. Peters, J.
P. Remon, C. Vervaet, J. Ketolainen, N. Sandler, J. Rantanen, K. Naelapää, T. De
Beer, Influence of raw material properties upon critical quality attributes of
continuously produced granules and tablets, Eur. J. Pharm. Biopharm. 87
(2014) 252–263, http://dx.doi.org/10.1016/j.ejpb.2014.02.011.
[72] I.P. Gabbott, F. Al Husban, G.K. Reynolds, The combined effect of wet
granulation process parameters and dried granule moisture content on tablet
quality attributes, Eur. J. Pharm. Biopharm. 106 (2016) 70–78, http://dx.doi.
org/10.1016/j.ejpb.2016.03.022.
[73] L. Shi, Y. Feng, C.C. Sun, Roles of Granule Size in Over-Granulation During
High Shear Wet Granulation, J. Pharm. Sci. 99 (2010) 3322–3325, http://dx.
doi.org/10.1002/jps.22118.
[74] A. Achanta, P.S. Adusumilli, K. James, Endpoint determination and its
relevance to physicochemical characteristics of solid dosage forms, in:
Symp. Granulation Process Endpoint Determ. Scale-up Pharm. R&D, 1997,
pp. 537–546.
[75] S. Watano, E. Numa, K. Miyanami, Y. Osako, On-line monitoring of granule
growth in high shear granulation by an image processing system, Chem.
Pharm. Bull. (Tokyo) 48 (2000) 1154–1159. http://www.ncbi.nlm.nih.gov/
pubmed/10959579.
[76] M. Whitaker, G.R. Baker, J. Westrup, P.A. Goulding, D.R. Rudd, R.M.
Belchamber, M.P. Collins, Application of acoustic emission to the
monitoring and end point determination of a high shear granulation
process, Int. J. Pharm. 205 (2000) 79–91, http://dx.doi.org/10.1016/S0378-
5173(00)00479-8.
[77] F. Osei-Yeboah, M. Zhang, Y. Feng, C.C. Sun, A formulation strategy for solving
the overgranulation problem in high shear wet granulation, J. Pharm. Sci. 103
(2014) 2434–2440, http://dx.doi.org/10.1002/jps.24066.
809
[78] D.A. Mota-Aguilar, C. Velázquez, Dynamics of the dry premixing stage of a
hydrophobic formulation and potential implications on the wet granulation
process, Powder Technol. 286 (2015) 318–324, http://dx.doi.org/10.1016/j.
powtec.2015.07.048.
[79] K.P. Hapgood, B. Khanmohammadi, Granulation of hydrophobic powders,
Powder Technol. 189 (2009) 253–262, http://dx.doi.org/10.1016/j.
powtec.2008.04.033.
[80] Z. Belohlav, L. Brenková, J. Hanika, P. Durdil, P. Rapek, V. Tomasek, Effect of
drug active substance particles on wet granulation process, Chem. Eng. Res.
Des. 85 (2007) 974–980, http://dx.doi.org/10.1205/cherd06205.
[81] T. Nguyen, W. Shen, K. Hapgood, Drop penetration time in heterogeneous
powder beds, Chem. Eng. Sci. 64 (2009) 5210–5221, http://dx.doi.org/
10.1016/j.ces.2009.08.038.
[82] D. Zhang, J. Flory, S. Panmai, U. Batra, M. Kaufman, Wettability of
pharmaceutical solids: its measurement and influence on wet granulation,
Colloids Surfaces A Physicochem. Eng. Asp. 206 (2002) 547–554, http://dx.
doi.org/10.1016/S0927-7757(02)00091-2.
[83] T.H. Nguyen, W. Shen, K. Hapgood, Effect of formulation hydrophobicity on
drug distribution in wet granulation, Chem. Eng. J. 164 (2010) 330–339,
http://dx.doi.org/10.1016/j.cej.2010.05.008.
[84] H. Charles-Williams, R. Wengeler, K. Flore, H. Feise, M.J. Hounslow, A.D.
Salman, Granulation behaviour of increasingly hydrophobic mixtures,
Powder Technol. 238 (2013) 64–76, http://dx.doi.org/10.1016/j.
powtec.2012.06.009.
[85] D. Smrčka, J. Dohnal, F. Štěpánek, Effect of process scale-up on the dissolution
of granules with a high content of active pharmaceutical ingredient, Powder
Technol. 285 (2015) 88–95, http://dx.doi.org/10.1016/j.powtec.2015.04.028.
[86] J. Li, B. Freireich, C. Wassgren, J.D. Litster, A general compartment-based
population balance model for particle coating and layered granulation, AIChE
J. 58 (2012) 1397–1408, http://dx.doi.org/10.1002/aic.12678.
[87] J. Litster, B. Ennis, The Science and Engineering of Granulation Processes,
Springer, Netherlands, Dordrecht (2004), http://dx.doi.org/10.1007/978-94-
017-0546-2.
[88] E. Horisawa, K. Danjo, H. Sunada, Influence of granulating method on physical
and mechanical properties, compression behavior, and compactibility of
lactose and microcrystalline cellulose granules, Drug Dev. Ind. Pharm. 26
(2000) 583–593, http://dx.doi.org/10.1081/DDC-100101273.
[89] J.Z. Gao, A. Jain, R. Motheram, D. Gray, M. Hussain, Fluid bed granulation of a
poorly water soluble, low density, micronized drug: comparison with high
shear granulation, Int. J. Pharm. 237 (2002) 1–14, http://dx.doi.org/10.1016/
S0378-5173(01)00982-6.
[90] D.S. Hausman, Comparison of low shear, high shear, and fluid bed granulation
during low dose tablet process development, Drug Dev. Ind. Pharm. 30 (2004)
259–266, http://dx.doi.org/10.1081/DDC-120030419.
[91] L. Mörl, S. Heinrich, M. Peglow, Fluidized bed spray granulation, Handb.
Powder Technol., Elsevier, Amsterdam, 2007.
[92] P. Roy, M. Vashishtha, R. Khanna, D. Subbarao, Heat and mass transfer study
in fluidized bed granulation—prediction of entry length, Particuology. 7
(2009) 215–219, http://dx.doi.org/10.1016/j.partic.2009.03.004.
[93] E. Teunou, D. Poncelet, Batch and continuous fluid bed coating – review and
state of the art, J. Food Eng. 53 (2002) 325–340, http://dx.doi.org/10.1016/
S0260-8774(01)00173-X.
[94] L. Fries, S. Antonyuk, S. Heinrich, D. Dopfer, S. Palzer, Collision dynamics in
fluidised bed granulators: a DEM-CFD study, Chem. Eng. Sci. 86 (2013) 108–
123, http://dx.doi.org/10.1016/j.ces.2012.06.026.
[95] S. Watano, Y. Imada, K. Hamada, Y. Wakamatsu, Y. Tanabe, R.N. Dave, R.
Pfeffer, Microgranulation of fine powders by a novel rotating fluidized bed
granulator, Powder Technol. 131 (2003) 250–255, http://dx.doi.org/10.1016/
S0032-5910(03)00007-X.
[96] S. Watano, H. Nakamura, K. Hamada, Y. Wakamatsu, Y. Tanabe, R.N. Dave, R.
Pfeffer, Fine particle coating by a novel rotating fluidized bed coater, Powder
Technol. 141 (2004) 172–176, http://dx.doi.org/10.1016/j.
powtec.2003.03.001.
[97] H. Nakamura, T. Kondo, S. Watano, Improvement of particle mixing and
fluidization quality in rotating fluidized bed by inclined injection of fluidizing
air, Chem. Eng. Sci. 91 (2013) 70–78, http://dx.doi.org/10.1016/j.
ces.2013.01.022.
[98] P. Eliaers, A. de Broqueville, A. Poortinga, T. van Hengstum, J. De Wilde, High-
G, low-temperature coating of cohesive particles in a vortex chamber, Powder
Technol. 258 (2014) 242–251, http://dx.doi.org/10.1016/j.
powtec.2014.03.033.
[99] H. Nakamura, N. Deguchi, S. Watano, Development of tapered rotating
fluidized bed granulator for increasing yield of granules, Adv. Powder
Technol. 26 (2015) 494–499, http://dx.doi.org/10.1016/j.apt.2014.12.003.
[100] Z.H. Loh, D.Z. Er, L.W. Chan, C.V. Liew, P.W. Heng, Spray granulation for drug
formulation, Expert Opin. Drug Deliv. 8 (2011) 1645–1661, http://dx.doi.org/
10.1517/17425247.2011.610304.
[101] U. Thurn, Dissertation no. 4511-Eidgenossischen Technischen, Hochschule,
Eidgenossischen Technischen, Zurich, 1970.
[102] M. Aulton, M. Banks, The factors affecting fluidised bed granulation, Manuf.
Chem. Aerosol. News 12 (1978) 50–56.
[103] F. Rowley, Effects of the bag shaking cycle on the particle size distribution of
granulation, Pharm. Technol. 13 (1989) 78–82.
[104] A. Seo, P. Holm, T. Schæfer, Effects of droplet size and type of binder on the
agglomerate growth mechanisms by melt agglomeration in a fluidised bed,
810 P. Suresh et al. / Chemical Engineering Journal 328 (2017) 785–815
Eur. J. Pharm. Sci. 16 (2002) 95–105, http://dx.doi.org/10.1016/S0928-0987
(02)00086-6.
[105] P. Rajniak, C. Mancinelli, R. Chern, F. Stepanek, L. Farber, B. Hill, Experimental
study of wet granulation in fluidized bed: Impact of the binder properties on
the granule morphology, Int. J. Pharm. 334 (2007) 92–102, http://dx.doi.org/
10.1016/j.ijpharm.2006.10.040.
[106] B. Michael, E.A. Michael, Fluidised-Bed Granulation: A Chronology, Drug Dev.
Ind. Pharm. 17 (1991) 1437–1463, http://dx.doi.org/10.3109/
03639049109026628.
[107] J. Litster, K. Hapgood, J. Michaels, A. Sims, M. Roberts, S. Kameneni, T. Hsu,
Liquid distribution in wet granulation: dimensionless spray flux, Powder
Technol. 114 (2001) 32–39, http://dx.doi.org/10.1016/S0032-5910(00)
00259-X.
[108] K.P. Hapgood, J.D. Litster, R. Smith, Nucleation regime map for liquid bound
granules, AIChE J. 49 (2003) 350–361, http://dx.doi.org/10.1002/
aic.690490207.
[109] M. Dadkhah, E. Tsotsas, Study of the morphology of solidified binder in spray
fluidized bed agglomerates by X-ray tomography, Powder Technol. 264
(2014) 256–264, http://dx.doi.org/10.1016/j.powtec.2014.05.037.
[110] H. Stahl, Comparing different granulation techniques, Pharm. Technol. Eur. 16
(2004) 23–33.
[111] C. Vervaet, J.P. Remon, Continuous granulation in the pharmaceutical
industry, Chem. Eng. Sci. 60 (2005) 3949–3957, http://dx.doi.org/10.1016/j.
ces.2005.02.028.
[112] Fluidized bed spray granulation, 2017, http://www.glatt.com/en/
processes/granulation/spray-granulation/ (accessed March 23, 2017).
[113] K. Masters, Spray Drying in Practice, Spray Dry Consult, 2002.
[114] R. Sherif, PhD Thesis, INPT, 1994.
[115] T.C. Seem, N.A. Rowson, A. Ingram, Z. Huang, S. Yu, M. de Matas, I. Gabbott, G.
K. Reynolds, Twin screw granulation—a literature review, Powder Technol.
276 (2015) 89–102, http://dx.doi.org/10.1016/j.powtec.2015.01.075.
[116] A. Kumar, J. Dhondt, J. Vercruysse, F. De Leersnyder, V. Vanhoorne, C. Vervaet,
J.P. Remon, K.V. Gernaey, T. De Beer, I. Nopens, Development of a process
map: A step towards a regime map for steady-state high shear wet twin
screw granulation, Powder Technol. 300 (2016) 73–82, http://dx.doi.org/
10.1016/j.powtec.2015.11.067.
[117] J. Vercruysse, A. Burggraeve, M. Fonteyne, P. Cappuyns, U. Delaet, I. Van
Assche, T. De Beer, J.P. Remon, C. Vervaet, Impact of screw configuration on
the particle size distribution of granules produced by twin screw granulation,
Int. J. Pharm. 479 (2015) 171–180, http://dx.doi.org/10.1016/j.
ijpharm.2014.12.071.
[118] P. Kleinebudde, A.J. Sølvberg, H. Lindner, The power-consumption-controlled
extruder: a tool for pellet production, J. Pharm. Pharmacol. 46 (1994) 542–
546, http://dx.doi.org/10.1111/j.2042-7158.1994.tb03853.x.
[119] N.-O. Lindberg, C. Tufvesson, P. Holm, L. Olbjer, Extrusion of an effervescent
granulation with a Twin Screw Extruder, Baker Perkins MPF 50 D. Influence
on intragranular porosity and liquid saturation, Drug Dev. Ind. Pharm. 14
(1988) 1791–1798, http://dx.doi.org/10.3109/03639048809151987.
[120] M.J. Gamlen, C. Eardley, Continuous extrusion using a raker Perkins MP50
(Multipurpose) extruder, Drug Dev. Ind. Pharm. 12 (1986) 1701–1713, http://
dx.doi.org/10.3109/03639048609042604.
[121] E. Keleb, A. Vermeire, C. Vervaet, J. Remon, Continuous twin screw extrusion
for the wet granulation of lactose, Int. J. Pharm. 239 (2002) 69–80, http://dx.
doi.org/10.1016/S0378-5173(02)00052-2.
[122] E. Keleb, Twin screw granulation as a simple and efficient tool for continuous
wet granulation, Int. J. Pharm. 273 (2004) 183–194, http://dx.doi.org/
10.1016/j.ijpharm.2004.01.001.
[123] E.I. Keleb, A. Vermeire, C. Vervaet, J.P. Remon, Single-step granulation/
tabletting of different grades of lactose: a comparison with high shear
granulation and compression, Eur. J. Pharm. Biopharm. 58 (2004) 77–82,
http://dx.doi.org/10.1016/j.ejpb.2004.03.007.
[124] B. Van Melkebeke, C. Vervaet, J.P. Remon, Validation of a continuous
granulation process using a twin-screw extruder, Int. J. Pharm. 356 (2008)
224–230, http://dx.doi.org/10.1016/j.ijpharm.2008.01.012.
[125] H. Li, M.R. Thompson, K.P. O’Donnell, Understanding wet granulation in the
kneading block of twin screw extruders, Chem. Eng. Sci. 113 (2014) 11–21,
http://dx.doi.org/10.1016/j.ces.2014.03.007.
[126] D. Djuric, P. Kleinebudde, Impact of screw elements on continuous
granulation with a twin-screw extruder, J. Pharm. Sci. 97 (2008) 4934–
4942, http://dx.doi.org/10.1002/jps.21339.
[127] A.S. El Hagrasy, J.D. Litster, Granulation rate processes in the kneading
elements of a twin screw granulator, AIChE J. 59 (2013) 4100–4115, http://
dx.doi.org/10.1002/aic.14180.
[128] M.R. Thompson, J. Sun, Wet granulation in a twin-screw extruder:
implications of screw design, J. Pharm. Sci. 99 (2010) 2090–2103, http://dx.
doi.org/10.1002/jps.21973.
[129] J. Vercruysse, D. Córdoba Díaz, E. Peeters, M. Fonteyne, U. Delaet, I. Van
Assche, T. De Beer, J.P. Remon, C. Vervaet, Continuous twin screw
granulation: Influence of process variables on granule and tablet quality,
Eur. J. Pharm. Biopharm. 82 (2012) 205–211, http://dx.doi.org/10.1016/j.
ejpb.2012.05.010.
[130] M.R. Thompson, S. Weatherley, R.N. Pukadyil, P.J. Sheskey, Foam granulation:
new developments in pharmaceutical solid oral dosage forms using twin
screw extrusion machinery, Drug Dev. Ind. Pharm. 38 (2012) 771–784, http://
dx.doi.org/10.3109/03639045.2011.633265.
[131] Y. Liu, M.R. Thompson, K.P. O’Donnell, N.S. Grasman, Effect of temperature on
the wetting behavior of hydroxypropyl methylcellulose in a twin-screw
granulator, Powder Technol. 302 (2016) 63–74, http://dx.doi.org/10.1016/j.
powtec.2016.08.032.
[132] E.I. Keleb, A. Vermeire, C. Vervaet, J.P. Remon, Extrusion granulation and high
shear granulation of different grades of lactose and highly dosed drugs: a
comparative study, Drug Dev. Ind. Pharm. 30 (2004) 679–691, http://dx.doi.
org/10.1081/DDC-120039338.
[133] H. Leuenberger, New trends in the production of pharmaceutical granules:
batch versus continuous processing, Eur. J. Pharm. Biopharm. 52 (2001) 289–
296, http://dx.doi.org/10.1016/S0939-6411(01)00199-0.
[134] M.R. Thompson, Twin screw granulation – review of current progress, Drug
Dev. Ind. Pharm. 41 (2015) 1223–1231, http://dx.doi.org/10.3109/
03639045.2014.983931.
[135] R.M. Dhenge, J.J. Cartwright, M.J. Hounslow, A.D. Salman, Twin screw wet
granulation: effects of properties of granulation liquid, Powder Technol. 229
(2012) 126–136, http://dx.doi.org/10.1016/j.powtec.2012.06.019.
[136] J.B. Wade, G.P. Martin, D.F. Long, Feasibility assessment for a novel reverse-
phase wet granulation process: the effect of liquid saturation and binder
liquid viscosity, Int. J. Pharm. 475 (2014) 450–461, http://dx.doi.org/10.1016/
j.ijpharm.2014.09.012.
[137] S.P. Nalawade, F. Picchioni, L.P.B.M. Janssen, Supercritical carbon dioxide as a
green solvent for processing polymer melts: processing aspects and
applications, Prog. Polym. Sci. 31 (2006) 19–43, http://dx.doi.org/10.1016/j.
progpolymsci.2005.08.002.
[138] M.E.P. McNally, F.V. Bright, Fundamental Studies and Applications of
Supercritical Fluids, 1992, pp. 1–15. doi:10.1021/bk-1992-0488.ch001.
[139] M. Pérez-Pérez, D. Suleiman, Development of a supercritical fluid CO2
granulator: effect of mixing and composition, Powder Technol. 305 (2017)
297–307, http://dx.doi.org/10.1016/j.powtec.2016.09.075.
[140] M. Dilip, Handbook of Pharmaceutical Granulation Technology, 3rd ed., CRC
Press, 2016.
[141] S. Shanmugam, Granulation techniques and technologies: recent progresses,
Bioimpacts. 5 (2015) 55–63, http://dx.doi.org/10.15171/bi.2015.04.
[142] P. Sheskey, C. Keary, P. Inbasekaran, Foam technology: the development of a
novel technique for the delivery of aqueous binder systems in high shear and
fluid-bed wet-granulation applications, in: AAPS Annu. Meet., 2003.
[143] M.X.L. Tan, K.P. Hapgood, Foam granulation: binder dispersion and
nucleation in mixer-granulators, Chem. Eng. Res. Des. 89 (2011) 526–536,
http://dx.doi.org/10.1016/j.cherd.2010.07.001.
[144] P. Sheskey, C. Keary, D. Clark, K. Balwinski, Scale-up trials of foam-
granulation technology – high shear, Pharm. Technol. Eur. 19 (2007) 37–46.
[145] P. Sheskey, C. Keary, P. Inbasekaren, U. Shrestha, K. Balwinski, Foamed
aqueous binders as carriers of low-dose drugs, in: 31st Annu. Meet. Control.
Release Soc., Hawaii, 2004.
[146] P. Sheskey, C. Keary, U. Shrestha, J. Becker, Use of a novel foam granulation
technique to incorporate low drug loading into intermediate release tablet
formulations, in: AAPS Annu. Meet., Baltimore, Maryland, USA, 2004.
[147] M.X.L. Tan, K.P. Hapgood, Foam granulation: effects of formulation and
process conditions on granule size distributions, Powder Technol. 218 (2012)
149–156, http://dx.doi.org/10.1016/j.powtec.2011.12.006.
[148] M.X.L. Tan, T.H. Nguyen, K.P. Hapgood, Drug distribution in wet granulation:
foam versus spray, Drug Dev. Ind. Pharm. 39 (2013) 1389–1400, http://dx.
doi.org/10.3109/03639045.2012.719233.
[149] O.M.Y. Koo, J. Ji, J. Li, Effect of powder substrate on foam drainage and
collapse: implications to foam granulation, J. Pharm. Sci. 101 (2012) 1385–
1390, http://dx.doi.org/10.1002/jps.23053.
[150] C. Cavallari, B. Abertini, M.L. González-Rodrı́guez, L. Rodriguez, Improved
dissolution behaviour of steam-granulated piroxicam, Eur. J. Pharm.
Biopharm. 54 (2002) 65–73, http://dx.doi.org/10.1016/S0939-6411(02)
00021-8.
[151] M. Vialpando, B. Albertini, N. Passerini, D. Bergers, P. Rombaut, J.A. Martens,
G. Van Den Mooter, Agglomeration of Mesoporous silica by melt and steam
granulation. Part I: A comparison between disordered and ordered
mesoporous silica, J. Pharm. Sci. 102 (2013) 3966–3977, http://dx.doi.org/
10.1002/jps.23700.
[152] M. Vialpando, B. Albertini, N. Passerini, Y. Vander Heyden, P. Rombaut, J.A.
Martens, G. Van Den Mooter, Agglomeration of mesoporous silica by melt
and steam granulation. Part II: Screening of steam granulation process
variables using a factorial design, J. Pharm. Sci. 102 (2013) 3978–3986, http://
dx.doi.org/10.1002/jps.23699.
[153] J.B. Wade, G.P. Martin, D.F. Long, The development of a growth regime map
for a novel reverse-phase wet granulation process, Int. J. Pharm. 512 (2016)
224–233, http://dx.doi.org/10.1016/j.ijpharm.2016.08.050.
[154] J.B. Wade, G.P. Martin, D.F. Long, The evolution of granule fracture strength as
a function of impeller tip speed and granule size for a novel reverse-phase
wet granulation process, Int. J. Pharm. 488 (2015) 95–101, http://dx.doi.org/
10.1016/j.ijpharm.2015.04.033.
[155] C.M. Keary, P.J. Sheskey, Preliminary report of the discovery of a new
pharmaceutical granulation process using foamed aqueous binders, Drug
Dev. Ind. Pharm. 30 (2004) 831–845, http://dx.doi.org/10.1081/DDC-
200030504.
[156] D. Rudd, Pharmacopoeial implications of continuous processes: new concepts
compared to batch processes, in: Process Anal. Technol., Cannes, France,
2004.
 P. Suresh et al. / Chemical Engineering Journal 328 (2017) 785–815
[157] L.X. Yu, Pharmaceutical quality by design: product and process development,
understanding, and control, Pharm. Res. 25 (2008) 781–791, http://dx.doi.
org/10.1007/s11095-007-9511-.
[158] U.S.D. of H. and H. Services, F. and D. Administration, C. for D.E. Research, C.
for B.E. and Research, Guidance for industry Q8 pharmaceutical development,
second revision, 2008, http://www.fda.gov/downloads/Drugs/Guidance
ComplianceRegulatoryInformation/%0AGuidances/ucm073507.pdf.%0A.
[159] G.E.P. Box, J.S. Hunter, W.G. Hunter, Statistics for Experimenters: An
Introduction to Design, Data Analysis and Model Building, John Wiley &
Sons, New York, 1978.
[160] S. Soravia, A. Orth, Design of experiments, in: Ullmann’s Encycl. Ind. Chem.,
Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2006, http://dx.
doi.org/10.1002/14356007.e08_e01.pub2.
[161] D. Košir, F. Vrečer, The performance of HPMC matrix tablets using various
agglomeration manufacturing processes, Drug Dev. Ind. Pharm. (2016) 1–9,
http://dx.doi.org/10.1080/03639045.2016.1249374.
[162] A. Crouter, L. Briens, The effect of moisture on the flowability of
pharmaceutical excipients, AAPS PharmSciTech. 15 (2014) 65–74, http://dx.
doi.org/10.1208/s12249-013-0036-0.
[163] C.C. Sun, Quantifying effects of moisture content on flow properties of
microcrystalline cellulose using a ring shear tester, Powder Technol. 289
(2016) 104–108, http://dx.doi.org/10.1016/j.powtec.2015.11.044.
[164] R. Ramachandran, J.M.-H. Poon, C.F.W. Sanders, T. Glaser, C.D. Immanuel, F.J.
Doyle, J.D. Litster, F. Stepanek, F.-Y. Wang, I.T. Cameron, Experimental studies
on distributions of granule size, binder content and porosity in batch drum
granulation: inferences on process modelling requirements and process
sensitivities, Powder Technol. 188 (2008) 89–101, http://dx.doi.org/10.1016/
j.powtec.2008.04.013.
[165] C. Drumm, M.M. Attarakih, H.-J. Bart, Coupling of CFD with DPBM for an RDC
extractor, Chem. Eng. Sci. 64 (2009) 721–732, http://dx.doi.org/10.1016/j.
ces.2008.05.041.
[166] J.A. Gantt, I.T. Cameron, J.D. Litster, E.P. Gatzke, Determination of coalescence
kernels for high-shear granulation using DEM simulations, Powder Technol.
170 (2006) 53–63, http://dx.doi.org/10.1016/j.powtec.2006.08.002.
[167] A. Adetayo, B. Ennis, A new approach to modeling granulation processes for
simulation and control purposes, Powder Technol. 108 (2000) 202–209,
http://dx.doi.org/10.1016/S0032-5910(99)00221-1.
[168] L.X. Liu, R. Smith, J.D. Litster, Wet granule breakage in a breakage only high-
hear mixer: Effect of formulation properties on breakage behaviour, Powder
Technol. 189 (2009) 158–164, http://dx.doi.org/10.1016/j.powtec. 2008.04.029.
[169] A. Jenike, Gravity Flow of Solids. Bulletin 108., Salt Lake City, 1961.
[170] C.F. Harwood, N. Pilpel, Granulation of Griseofulvin, J. Pharm. Sci. 57 (1968)
478–481, http://dx.doi.org/10.1002/jps.2600570325.
[171] D. Ganderton, B.M. Hunter, A comparison of granules prepared by pan
granulation and by massing and screening, J. Pharm. Pharmacol. 23 (1971)
1S–10S, http://dx.doi.org/10.1111/j.2042-7158.1971.tb08762.x.
[172] G. Gold, R.N. Duvall, B.T. Palermo, J.G. Slater, Powder flow studies II, J. Pharm.
Sci. 55 (1966) 1291–1295, http://dx.doi.org/10.1002/jps.2600551125.
[173] H. Rumpf, Agglomeration, Interscience, New York, 1962.
[174] A. Mehta, M.A. Zoglio, J.T. Carstensen, Ball milling as a measure of crushing
stength of granules, J. Pharm. Sci. 67 (1978) 905–908, 660504.
[175] M. Serpelloni, J.-P. Boonaert, Pulverulent mannitol of moderate friability and
process for its preparation, US5573777A, 1996.
[176] S. Brunauer, P.H. Emmett, E. Teller, Adsorption of gases in multimolecular
layers, J. Am. Chem. Soc. 60 (1938) 309–319, http://dx.doi.org/
10.1021/ja01269a023.
[177] Z.T. Chowhan, Moisture, hardness, disintegration and dissolution
interrelationships in compressed tablets prepared by the wet granulation
process, Drug Dev. Ind. Pharm. 5 (1979) 41–62, http://dx.doi.org/10.3109/
03639047909055661.
[178] Á. Hegedu } s, K. Pintye-Hódi, Influence of the type of the high-shear
granulator on the physico-chemical properties of granules, Chem. Eng.
Process. Process Intensif. 46 (2007) 1012–1019, http://dx.doi.org/10.1016/
j.cep.2007.05.017.
[179] J. Carstensen, Pharmaceutical Principles of Solid Dosage Forms, Technomic
Publishing, Lancaster, 1993.
[180] R. Suryanarayanan, X-Ray Powder diffractometry, Phys. Charact. Pharm.
Solids, Informa Healthcare, New York, 1995.
[181] Y.T. Makkawi, P.C. Wright, Electrical capacitance tomography for
conventional fluidized bed measurements—remarks on the measuring
technique, Powder Technol. 148 (2004) 142–157, http://dx.doi.org/10.1016/
j.powtec.2004.09.006.
[182] D.M. Koller, A. Posch, G. Hörl, C. Voura, S. Radl, N. Urbanetz, S.D. Fraser, W.
Tritthart, F. Reiter, M. Schlingmann, J.G. Khinast, Continuous quantitative
monitoring of powder mixing dynamics by near-infrared spectroscopy,
Powder Technol. 205 (2011) 87–96, http://dx.doi.org/10.1016/j.
powtec.2010.08.070.
[183] C. Wightman, F.J. Muzzio, J. Wilder, A quantitative image analysis method for
characterizing mixtures of granular materials, Powder Technol. 89 (1996)
165–176, http://dx.doi.org/10.1016/S0032-5910(96)03178-6.
[184] S. Muerza, H. Berthiaux, S. Massol-Chaudeur, G. Thomas, A dynamic study of
static mixing using on-line image analysis, Powder Technol. 128 (2002) 195–
204, http://dx.doi.org/10.1016/S0032-5910(02)00197-3.
[185] D.S. Hausman, R.T. Cambron, A. Sakr, Application of Raman spectroscopy for
on-line monitoring of low dose blend uniformity, Int. J. Pharm. 298 (2005)
80–90, http://dx.doi.org/10.1016/j.ijpharm.2005.04.011.
811
[186] H.W. Ward, D.O. Blackwood, M. Polizzi, H. Clarke, Monitoring blend potency
in a tablet press feed frame using near infrared spectroscopy, J. Pharm.
Biomed. Anal. 80 (2013) 18–23, http://dx.doi.org/10.1016/j.jpba.2013.02.008.
[187] A.U. Vanarase, M. Alcalà, J.I. Jerez Rozo, F.J. Muzzio, R.J. Romañach, Real-time
monitoring of drug concentration in a continuous powder mixing process
using NIR spectroscopy, Chem. Eng. Sci. 65 (2010) 5728–5733, http://dx.doi.
org/10.1016/j.ces.2010.01.036.
[188] C. Ravn, E. Skibsted, R. Bro, Near-infrared chemical imaging (NIR-CI) on
pharmaceutical solid dosage forms—comparing common calibration
approaches, J. Pharm. Biomed. Anal. 48 (2008) 554–561, http://dx.doi.org/
10.1016/j.jpba.2008.07.019.
[189] L. Chablani, M.K. Taylor, A. Mehrotra, P. Rameas, W.C. Stagner, Inline real-
time near-infrared granule moisture measurements of a continuous
granulation–drying–milling process, AAPS PharmSciTech. 12 (2011) 1050–
1055, http://dx.doi.org/10.1208/s12249-011-9669-z.
[190] E.H. Hardy, J. Hoferer, G. Kasper, The mixing state of fine powders measured
by magnetic resonance imaging, Powder Technol. 177 (2007) 12–22, http://
dx.doi.org/10.1016/j.powtec.2007.02.042.
[191] J.R. Jones, J. Bridgwater, A case study of particle mixing in a ploughshare
mixer using Positron Emission Particle Tracking, Int. J. Miner. Process. 53
(1998) 29–38, http://dx.doi.org/10.1016/S0301-7516(97)00054-9.
[192] R. Forster, J. Seville, D. Parker, Y. Ding, Tracking single particles in process
equipment or probing processes using positrons, KONA Powder Part J. 18
(2000) 139–148, http://dx.doi.org/10.14356/kona.2000020.
[193] G. Léonard, F. Bertrand, J. Chaouki, P.M. Gosselin, An experimental
investigation of effusivity as an indicator of powder blend uniformity,
Powder Technol. 181 (2008) 149–159, http://dx.doi.org/10.1016/j.
powtec.2006.12.007.
[194] S. Watano, Chapter 10 Online monitoring, Handb. Powder Technol., 2007, pp.
477–498. doi: 10.1016/S0167-3785(07)80045-5.
[195] A.S. El Hagrasy, P. Cruise, I. Jones, J.D. Litster, In-line size monitoring of a twin
screw granulation process using high-speed imaging, J. Pharm. Innov. 8
(2013) 90–98, http://dx.doi.org/10.1007/s12247-013-9149-y.
[196] A. Kumar, J. Dhondt, F. De Leersnyder, J. Vercruysse, V. Vanhoorne, C. Vervaet,
J.P. Remon, K.V. Gernaey, T. De Beer, I. Nopens, Evaluation of an in-line
particle imaging tool for monitoring twin-screw granulation performance,
Powder Technol. 285 (2015) 80–87, http://dx.doi.org/10.1016/j.
powtec.2015.05.031.
[197] V. Corvari, W.C. Fry, W.L. Seibert, L. Augsburger, Instrumentation of a high-
shear mixer: evaluation and comparison of a new capacitive sensor, a watt
meter, and a strain-gage torque sensor for wet granulation monitoring,
Pharm. Res. 9 (1992) 1525–1533. http://www.ncbi.nlm.nih.gov/pubmed/
1488393.
[198] J. Luypaert, D.L. Massart, Y. Vander Heyden, Near-infrared spectroscopy
applications in pharmaceutical analysis, Talanta 72 (2007) 865–883, http://
dx.doi.org/10.1016/j.talanta. 2006.12.023.
[199] K.M. Morisseau, C.T. Rhodes, Pharmaceutical uses of near-infrared
spectroscopy, Drug Dev. Ind. Pharm. 21 (1995) 1071–1090, http://dx.doi.
org/10.3109/03639049509069804.
[200] J. Rantanen, In-line moisture measurement during granulation with a four-
wavelength near infrared sensor: an evaluation of particle size and binder
effects, Eur. J. Pharm. Biopharm. 50 (2000) 271–276, http://dx.doi.org/
10.1016/S0939-6411(00)00096-5.
[201] P. Frake, D. Greenhalgh, S.M. Grierson, J.M. Hempenstall, D.R. Rudd, Process
control and end-point determination of a fluid bed granulation by application
of near infra-red spectroscopy, Int. J. Pharm. 151 (1997) 75–80, http://dx.doi.
org/10.1016/S0378-5173(97)04894-1.
[202] J. Rantanen, S. Lehtola, P. Rämet, J.-P. Mannermaa, J. Yliruusi, On-line
monitoring of moisture content in an instrumented fluidized bed
granulator with a multi-channel NIR moisture sensor, Powder Technol. 99
(1998) 163–170, http://dx.doi.org/10.1016/S0032-5910(98)00100-4.
[203] A. Miwa, T. Yajima, S. Itai, Prediction of suitable amount of water addition for
wet granulation, Int. J. Pharm. 195 (2000) 81–92, http://dx.doi.org/10.1016/
S0378-5173(99)00376-2.
[204] A. Miwa, T. Yajima, H. Ikuta, K. Makado, Prediction of suitable amounts of
water in fluidized bed granulation of pharmaceutical formulations using
corresponding values of components, Int. J. Pharm. 352 (2008) 202–208,
http://dx.doi.org/10.1016/j.ijpharm.2007.10.044.
[205] A.C. Jørgensen, P. Luukkonen, J. Rantanen, T. Schæfer, A.M. Juppo, J. Yliruusi,
Comparison of torque measurements and near-infrared spectroscopy in
characterization of a wet granulation process, J. Pharm. Sci. 93 (2004) 2232–
2243, http://dx.doi.org/10.1002/jps.20132.
[206] J. Rantanen, Process analytical applications of Raman spectroscopy, J. Pharm.
Pharmacol. 59 (2007) 171–177, http://dx.doi.org/10.1211/jpp.59.2.0004.
[207] H. Wikström, I.R. Lewis, L.S. Taylor, Comparison of sampling techniques for
in-line monitoring using Raman spectroscopy, Appl. Spectrosc. 59 (2005)
934–941, http://dx.doi.org/10.1366/0003702054411553.
[208] D. Scheibli, The use of FBRM for on-line particle size analysis in a fluid bed
granulator, San Jose State University, 2007, http://scholarworks.sjsu.edu/
etd_theses/3576/.
[209] A.T. Tok, X. Goh, W.K. Ng, R.B.H. Tan, monitoring granulation rate processes
using three PAT tools in a pilot-scale fluidized bed, AAPS PharmSciTech. 9
(2008) 1083–1091, http://dx.doi.org/10.1208/s12249-008-9145-6.
[210] X. Hu, J.C. Cunningham, D. Winstead, Study growth kinetics in fluidized bed
granulation with at-line FBRM, Int. J. Pharm. 347 (2008) 54–61, http://dx.doi.
org/10.1016/j.ijpharm.2007.06.043.
812 P. Suresh et al. / Chemical Engineering Journal 328 (2017) 785–815
[211] N. Kail, W. Marquardt, H. Briesen, Process analysis by means of focused beam
reflectance measurements, Ind. Eng. Chem. Res. 48 (2009) 2936–2946, http://
dx.doi.org/10.1021/ie800839s.
[212] A. Ruf, J. Worlitschek, M. Mazzotti, Modeling and Experimental Analysis of
PSD Measurements through FBRM <167::AID-PPSC167>3.0.CO;2-T Part. Part.
Syst. Charact. 17 (2000) 167–179, http://dx.doi.org/10.1002/1521-4117
(200012)17:4.
[213] C.A.M. da Silva, J.J. Butzge, M. Nitz, O.P. Taranto, Monitoring and control of
coating and granulation processes in fluidized beds – a review, Adv. Powder
Technol. 25 (2014) 195–210, http://dx.doi.org/10.1016/j.apt.2013.04.008.
[214] D. Petrak, Simultaneous measurement of particle size and particle velocity by
the spatial filtering technique, Part. Part. Syst. Charact. 19 (2002) 391–400,
http://dx.doi.org/10.1002/ppsc.200290002.
[215] D. Petrak, H. Rauh, Optical probe for the in-line determination of particle
shape, size, and velocity, Part. Sci. Technol. 24 (2006) 381–394, http://dx.doi.
org/10.1080/02726350600934622.
[216] T. Närvänen, T. Lipsanen, O. Antikainen, H. Räikkönen, J. Heinämäki, J.
Yliruusi, Gaining fluid bed process understanding by in-line particle size
analysis, J. Pharm. Sci. 98 (2009) 1110–1117, http://dx.doi.org/10.1002/
jps.21486.
[217] A. Burggraeve, T. Van Den Kerkhof, M. Hellings, J.P. Remon, C. Vervaet, T. De
Beer, Evaluation of in-line spatial filter velocimetry as PAT monitoring tool
for particle growth during fluid bed granulation, Eur. J. Pharm. Biopharm. 76
(2010) 138–146, http://dx.doi.org/10.1016/j.ejpb.2010.06.001.
[218] A. Burggraeve, T. Van den Kerkhof, M. Hellings, J.P. Remon, C. Vervaet, T. De
Beer, Batch statistical process control of a fluid bed granulation process using
in-line spatial filter velocimetry and product temperature measurements,
Eur. J. Pharm. Sci. 42 (2011) 584–592, http://dx.doi.org/10.1016/j.
ejps.2011.03.002.
[219] J. Huang, C. Goolcharran, J. Utz, P. Hernandez-Abad, K. Ghosh, A. Nagi, A PAT
approach to enhance process understanding of fluid bed granulation using in-
line particle size characterization and multivariate analysis, J. Pharm. Innov. 5
(2010) 58–68, http://dx.doi.org/10.1007/s12247-010-9079-x.
[220] L. Gradinarsky, H. Brage, B. Lagerholm, I.N. Björn, S. Folestad, In situ
monitoring and control of moisture content in pharmaceutical powder
processes using an open-ended coaxial probe, Meas. Sci. Technol. 17 (2006)
1847–1853, http://dx.doi.org/10.1088/0957-0233/17/7/024.
[221] H. Tsujimoto, T. Yokoyama, C. Huang, I. Sekiguchi, Monitoring particle
fluidization in a fluidized bed granulator with an acoustic emission sensor,
Powder Technol. 113 (2000) 88–96, http://dx.doi.org/10.1016/S0032-5910
(00)00205-9.
[222] M. Halstensen, K. Esbensen, New developments in acoustic chemometric
prediction of particle size distribution—the problem is the solution, J.
Chemom. 14 (2000) 463–481, http://dx.doi.org/10.1002/1099-128X
(200009/12)14:5/6, <463::AID-CEM628>3.0.CO;2-Y.
[223] M. Halstensen, P. de Bakker, K.H. Esbensen, Acoustic chemometric
monitoring of an industrial granulation production process—a PAT
feasibility study, Chemom. Intell. Lab. Syst. 84 (2006) 88–97, http://dx.doi.
org/10.1016/j.chemolab.2006.05.012.
[224] J.N. Staniforth, S. Walker, P. Flanders, Granulation monitoring in a high speed
mixer/processor using a probe vibration analysis technique, Int. J. Pharm. 31
(1986) 277–280, http://dx.doi.org/10.1016/0378-5173(86)90163-8.
[225] J.N. Staniforth, S.M. Quincey, Granulation monitoring in a planetary mixer
using a probe vibration analysis technique, Int. J. Pharm. 32 (1986) 177–185,
http://dx.doi.org/10.1016/0378-5173(86)90177-8.
[226] D. Daniher, L. Briens, A. Tallevi, End-point detection in high-shear granulation
using sound and vibration signal analysis, Powder Technol. 181 (2008) 130–
136, http://dx.doi.org/10.1016/j.powtec.2006.12.003.
[227] L. Briens, D. Daniher, A. Tallevi, Monitoring high-shear granulation using
sound and vibration measurements, Int. J. Pharm. 331 (2007) 54–60, http://
dx.doi.org/10.1016/j.ijpharm.2006.09.012.
[228] I. Talu, G.I. Tardos, J. Ruud van Ommen, Use of stress fluctuations to monitor
wet granulation of powders, Powder Technol. 117 (2001) 149–162, http://dx.
doi.org/10.1016/S0032-5910(01)00321-7.
[229] L. Feng, M. Liu, J. Wang, J. Sun, J. Wang, Y. Mao, Study on the flow instability of
a spray granulation tower, Sep. Purif. Technol. 169 (2016) 210–222, http://dx.
doi.org/10.1016/j.seppur.2016.04.045.
[230] T. Hagemeier, M. Börner, A. Bück, E. Tsotsas, A comparative study on optical
techniques for the estimation of granular flow velocities, Chem. Eng. Sci. 131
(2015) 63–75, http://dx.doi.org/10.1016/j.ces.2015.03.045.
[231] L. Nikiforaki, G. Montante, K. Lee, M. Yianneskis, On the origin, frequency and
magnitude of macro-instabilities of the flows in stirred vessels, Chem. Eng.
Sci. 58 (2003) 2937–2949, http://dx.doi.org/10.1016/S0009-2509(03)00152-
0.
[232] Y. Liu, Q. Yang, P. Qian, H. Wang, Experimental study of circulation flow in a
light dispersion hydrocyclone, Sep. Purif. Technol. 137 (2014) 66–73, http://
dx.doi.org/10.1016/j.seppur.2014.09.020.
[233] Z. Li, M. Kind, G. Gruenewald, Modeling fluid dynamics and growth kinetics in
fluidized bed spray granulation, J. Comput. Multiph. Flows. 2 (2010) 235–248,
http://dx.doi.org/10.1260/1757-482X.2.4.235.
[234] B.P. Hoomans, J.A. Kuipers, M. Mohd Salleh, M. Stein, J.P. Seville, Experimental
validation of granular dynamics simulations of gas-fluidised beds with
homogenous in-flow conditions using Positron Emission Particle Tracking,
Powder Technol. 116 (2001) 166–177, http://dx.doi.org/10.1016/S0032-5910
(00)00391-0.
[235] R.W. Breault, C.J. Ludlow, P.C. Yue, Cluster particle number and granular
temperature for cork particles at the wall in the riser of a CFB, Powder
Technol. 149 (2005) 68–77, http://dx.doi.org/10.1016/j.powtec.2004.11.003.
[236] A.M. Bouwman, M.J. Henstra, D. Westerman, J.T. Chung, Z. Zhang, A. Ingram, J.
P.K. Seville, H.W. Frijlink, The effect of the amount of binder liquid on the
granulation mechanisms and structure of microcrystalline cellulose granules
prepared by high shear granulation, Int. J. Pharm. 290 (2005) 129–136, http://
dx.doi.org/10.1016/j.ijpharm.2004.11.024.
[237] D.J. Parker, X. Fan, Positron emission particle tracking—application and
labelling techniques, Particuology. 6 (2008) 16–23, http://dx.doi.org/
10.1016/j.cpart.2007.10.004.
[238] X. Fan, D.J. Parker, M.D. Smith, Labelling a single particle for positron
emission particle tracking using direct activation and ion-exchange
techniques, Nucl. Instruments Methods Phys. Res. Sect. A Accel.
Spectrometers, Detect. Assoc. Equip. 562 (2006) 345–350, http://dx.doi.org/
10.1016/j.nima.2006.03.015.
[239] K.T. Lee, A. Ingram, N.A. Rowson, Twin screw wet granulation: the study of a
continuous twin screw granulator using Positron Emission Particle Tracking
(PEPT) technique, Eur. J. Pharm. Biopharm. 81 (2012) 666–673, http://dx.doi.
org/10.1016/j.ejpb.2012.04.011.
[240] K.V. Gernaey, A.E. Cervera-Padrell, J.M. Woodley, A perspective on PSE in
pharmaceutical process development and innovation, Comput. Chem. Eng. 42
(2012) 15–29, http://dx.doi.org/10.1016/j.compchemeng.2012.02.022.
[241] E.P. Gatzke, F.J. Doyle, Model predictive control of a granulation system using
soft output constraints and prioritized control objectives, Powder Technol.
121 (2001) 149–158, http://dx.doi.org/10.1016/S0032-5910(01)00334-5.
[242] P.R. Mort, S.W. Capeci, J.W. Holder, Control of agglomerate attributes in a
continuous binder-agglomeration process, Powder Technol. 117 (2001) 173–
176, http://dx.doi.org/10.1016/S0032-5910(01)00323-0.
[243] F.Y. Wang, I.T. Cameron, Review and future directions in the modelling and
control of continuous drum granulation, Powder Technol. 124 (2002) 238–
253, http://dx.doi.org/10.1016/S0032-5910(02)00020-7.
[244] K.-U. Klatt, W. Marquardt, Perspectives for process systems engineering—
personal views from academia and industry, Comput. Chem. Eng. 33 (2009)
536–550, http://dx.doi.org/10.1016/j.compchemeng.2008.09.002.
[245] M.T. am Ende, R. Bharadwaj, S. García-Muñoz, W. Ketterhagen, A. Prpich, P.
Doshi, Process modeling techniques and applications for solid oral drug
products, in: Chem. Eng. Pharm. Ind., John Wiley & Sons, Inc., Hoboken, NJ,
USA, 2010, pp. 633–662, http://dx.doi.org/10.1002/9780470882221.ch34.
[246] P.R. Mort, Scale-up of binder agglomeration processes, Powder Technol. 150
(2005) 86–103, http://dx.doi.org/10.1016/j.powtec.2004.11.025.
[247] M. Bardin, P. Knight, J.P. Seville, On control of particle size distribution in
granulation using high-shear mixers, Powder Technol. 140 (2004) 169–175,
http://dx.doi.org/10.1016/j.powtec.2004.03.003.
[248] A.S. Rankell, M.W. Scott, H.A. Lieberman, F.S. Chow, J.V. Battista, Continuous
production of tablet granulations in a fluidized bed II, J. Pharm. Sci. 53 (1964)
320–324, http://dx.doi.org/10.1002/jps.2600530316.
[249] G.I. Tardos, M.I. Khan, P.R. Mort, Critical parameters and limiting conditions
in binder granulation of fine powders, Powder Technol. 94 (1997) 245–258,
http://dx.doi.org/10.1016/S0032-5910(97)03321-4.
[250] S.H. Schaafsma, N.W.F. Kossen, M.T. Mos, L. Blauw, A.C. Hoffmann, Effects and
control of humidity and particle mixing in fluid-bed granulation, AIChE J. 45
(1999) 1202–1210, http://dx.doi.org/10.1002/aic.690450606.
[251] K.P. Hapgood, J.D. Litster, E.T. White, P.R. Mort, D.G. Jones, Dimensionless
spray flux in wet granulation: Monte-Carlo simulations and experimental
validation, Powder Technol. 141 (2004) 20–30, http://dx.doi.org/10.1016/j.
powtec.2004.02.005.
[252] W.J. Wildeboer, J.D. Litster, I.T. Cameron, Modelling nucleation in wet
granulation, Chem. Eng. Sci. 60 (2005) 3751–3761, http://dx.doi.org/
10.1016/j.ces.2005.02.005.
[253] C.A. Biggs, C. Sanders, A.C. Scott, A.W. Willemse, A.C. Hoffman, T. Instone, A.D.
Salman, M.J. Hounslow, Coupling granule properties and granulation rates in
high-shear granulation, Powder Technol. 130 (2003) 162–168, http://dx.doi.
org/10.1016/S0032-5910(02)00260-7.
[254] C.D. Immanuel, F.J. Doyle, Solution technique for a multi-dimensional
population balance model describing granulation processes, Powder
Technol. 156 (2005) 213–225, http://dx.doi.org/10.1016/j.
powtec.2005.04.013.
[255] C.F. Sanders, A. Willemse, A. Salman, M. Hounslow, Development of a
predictive high-shear granulation model, Powder Technol. 138 (2003) 18–24,
http://dx.doi.org/10.1016/j.powtec.2003.08.046.
[256] D.L. Marchisio, R.O. Fox, Solution of population balance equations using the
direct quadrature method of moments, J. Aerosol Sci. 36 (2005) 43–73, http://
dx.doi.org/10.1016/j.jaerosci.2004.07.009.
[257] I.T. Cameron, F.Y. Wang, C.D. Immanuel, F. Stepanek, Process systems
modelling and applications in granulation: a review, Chem. Eng. Sci. 60
(2005) 3723–3750, http://dx.doi.org/10.1016/j.ces.2005.02.004.
[258] J.M.-H. Poon, C.D. Immanuel, F.J. Doyle III, J.D. Litster, A three-dimensional
population balance model of granulation with a mechanistic representation
of the nucleation and aggregation phenomena, Chem. Eng. Sci. 63 (2008)
1315–1329, http://dx.doi.org/10.1016/j.ces.2007.07.048.
 P. Suresh et al. / Chemical Engineering Journal 328 (2017) 785–815
[259] D. Barrasso, A. El Hagrasy, J.D. Litster, R. Ramachandran, Multi-dimensional
population balance model development and validation for a twin screw
granulation process, Powder Technol. 270 (2015) 612–621, http://dx.doi.org/
10.1016/j.powtec.2014.06.035.
[260] A. Braumann, M. Kraft, P.R. Mort, Parameter estimation in a multidimensional
granulation model, Powder Technol. 197 (2010) 196–210, http://dx.doi.org/
10.1016/j.powtec.2009.09.014.
[261] A. Chaudhury, D. Barrasso, P. Pandey, H. Wu, R. Ramachandran, Population
balance model development, validation, and prediction of CQAs of a high-
shear wet granulation process: towards QbD in drug product pharmaceutical
manufacturing, J. Pharm. Innov. 9 (2014) 53–64, http://dx.doi.org/10.1007/
s12247-014-9172-7.
[262] R. Ramachandran, P.I. Barton, Effective parameter estimation within a multi-
dimensional population balance model framework, Chem. Eng. Sci. 65 (2010)
4884–4893, http://dx.doi.org/10.1016/j.ces.2010.05.039.
[263] P.A. Cundall, O.D.L. Strack, A discrete numerical model for granular
assemblies, Géotechnique. 29 (1979) 47–65, http://dx.doi.org/
10.1680/geot.1979.29.1.47.
[264] D. Barrasso, R. Ramachandran, Qualitative assessment of a multi-scale,
compartmental PBM-DEM Model of a continuous twin-screw wet
granulation process, J. Pharm. Innov. 11 (2016) 231–249, http://dx.doi.org/
10.1007/s12247-015-9240-7.
[265] D. Barrasso, T. Eppinger, F.E. Pereira, R. Aglave, K. Debus, S.K. Bermingham, R.
Ramachandran, A multi-scale, mechanistic model of a wet granulation
process using a novel bi-directional PBM–DEM coupling algorithm, Chem.
Eng. Sci. 123 (2015) 500–513, http://dx.doi.org/10.1016/j.ces.2014.11.011.
[266] D. Barrasso, R. Ramachandran, Multi-scale modeling of granulation
processes: Bi-directional coupling of PBM with DEM via collision
frequencies, Chem. Eng. Res. Des. 93 (2015) 304–317, http://dx.doi.org/
10.1016/j.cherd.2014.04.016.
[267] K.V.S. Sastry, Similarity size distribution of agglomerates during their growth
by coalescence in granulation or green pelletization, Int. J. Miner. Process. 2
(1975) 187–203, http://dx.doi.org/10.1016/0301-7516(75)90021-6.
[268] P.C. Kapur, A coalescence model for granulation, Iandec Process Des. Dev. 8
(1969) 51–56.
[269] A. Braumann, M.J. Goodson, M. Kraft, P.R. Mort, Modelling and validation of
granulation with heterogeneous binder dispersion and chemical reaction,
Chem. Eng. Sci. 62 (2007) 4717–4728, http://dx.doi.org/10.1016/j.
ces.2007.05.028.
[270] A. Darelius, A. Rasmuson, I.N. Björn, S. Folestad, High shear wet granulation
modelling—a mechanistic approach using population balances, Powder
Technol. 160 (2005) 209–218, http://dx.doi.org/10.1016/j.powtec.
2005.08.036.
[271] J.A. Gantt, E.P. Gatzke, High-shear granulation modeling using a discrete
element simulation approach, Powder Technol. 156 (2005) 195–212, http://
dx.doi.org/10.1016/j.powtec.2005.04.012.
[272] W.R. Ketterhagen, M.T. am Ende, B.C. Hancock, Process modeling in the
pharmaceutical industry using the discrete element method, J. Pharm. Sci. 98
(2009) 442–470, http://dx.doi.org/10.1002/jps.21466.
[273] H.P. Zhu, Z.Y. Zhou, R.Y. Yang, A.B. Yu, Discrete particle simulation of
particulate systems: A review of major applications and findings,
Chem. Eng. Sci. 63 (2008) 5728–5770, http://dx.doi.org/10.1016/j.
ces.2008.08.006.
[274] H.J. Herrmann, S. Luding, Modeling granular media on the computer, Contin.
Mech. Thermodyn. 10 (1998) 189–231.
[275] P.Y. Liu, R.Y. Yang, A.B. Yu, DEM study of the transverse mixing of wet
particles in rotating drums, Chem. Eng. Sci. 86 (2013) 99–107, http://dx.doi.
org/10.1016/j.ces.2012.06.015.
[276] D. Barrasso, A. Tamrakar, R. Ramachandran, A reduced order PBM–ANN
model of a multi-scale PBM–DEM description of a wet granulation process,
Chem. Eng. Sci. 119 (2014) 319–329, http://dx.doi.org/10.1016/j.
ces.2014.08.005.
[277] H. Nakamura, H. Fujii, S. Watano, Scale-up of high shear mixer-granulator
based on discrete element analysis, Powder Technol. 236 (2013) 149–156,
http://dx.doi.org/10.1016/j.powtec.2012.03.009.
[278] G. Lian, C. Thornton, M.J. Adams, Discrete particle simulation of agglomerate
impact coalescence, Chem. Eng. Sci. 53 (1998) 3381–3391, http://dx.doi.org/
10.1016/S0009-2509(98)00152-3.
[279] A. Reinhold, H. Briesen, Numerical behavior of a multiscale aggregation
model—coupling population balances and discrete element models, Chem.
Eng. Sci. 70 (2012) 165–175, http://dx.doi.org/10.1016/j.ces.2011.06.041.
[280] F. Štěpánek, P. Rajniak, C. Mancinelli, R.T. Chern, R. Ramachandran,
Distribution and accessibility of binder in wet granules, Powder Technol.
189 (2009) 376–384, http://dx.doi.org/10.1016/j.powtec.2008.04.015.
[281] A.A. Adetayo, J.D. Litster, S.E. Pratsinis, B.J. Ennis, Population balance
modelling of drum granulation of materials with wide size distribution,
Powder Technol. 82 (1995) 37–49, http://dx.doi.org/10.1016/0032-5910(94)
02896-V.
[282] A.A. Adetayo, B.J. Ennis, Unifying approach to modeling granule coalescence
mechanisms, AIChE J. 43 (1997) 927–934, http://dx.doi.org/10.1002/
aic.690430408.
[283] M. Hounslow, The population balance as a tool for understanding particle
rate processes, KONA Powder Part J. 16 (1998) 179–193, http://dx.doi.org/
10.14356/kona.1998021.
813
[284] S.A. Cryer, Modeling agglomeration processes in fluid-bed granulation, AIChE
J. 45 (1999) 2069–2078, http://dx.doi.org/10.1002/aic.690451005.
[285] R. Ramachandran, C.D. Immanuel, F. Stepanek, J.D. Litster, F.J. Doyle, A
mechanistic model for breakage in population balances of granulation:
Theoretical kernel development and experimental validation, Chem. Eng. Res.
Des. 87 (2009) 598–614, http://dx.doi.org/10.1016/j.cherd.2008.11.007.
[286] M. Kostoglou, Chapter 18 The Linear Breakage Equation: From Fundamental
Issues to Numerical Solution Techniques, 2007, pp. 793–835. doi:10.1016/
S0167-3785(07)12021-2.
[287] R. Ramachandran, A. Chaudhury, Model-based design and control of a
continuous drum granulation process, Chem. Eng. Res. Des. 90 (2012) 1063–
1073, http://dx.doi.org/10.1016/j.cherd.2011.10.022.
[288] J.M.-H. Poon, R. Ramachandran, C.F.W. Sanders, T. Glaser, C.D. Immanuel, F.J.
Doyle III, J.D. Litster, F. Stepanek, F.-Y. Wang, I.T. Cameron, Experimental
validation studies on a multi-dimensional and multi-scale population
balance model of batch granulation, Chem. Eng. Sci. 64 (2009) 775–786,
http://dx.doi.org/10.1016/j.ces.2008.08.037.
[289] K. Washino, H.S. Tan, M.J. Hounslow, A.D. Salman, Meso-scale coupling model
of DEM and CIP for nucleation processes in wet granulation, Chem. Eng. Sci.
86 (2013) 25–37, http://dx.doi.org/10.1016/j.ces.2012.04.020.
[290] K. Washino, H.S. Tan, M.J. Hounslow, A.D. Salman, A new capillary force
model implemented in micro-scale CFD–DEM coupling for wet granulation,
Chem. Eng. Sci. 93 (2013) 197–205, http://dx.doi.org/10.1016/j.
ces.2013.02.006.
[291] X. Yu, M.J. Hounslow, G.K. Reynolds, A. Rasmuson, I. Niklasson Björn, P.J.
Abrahamsson, A compartmental CFD-PBM model of high shear wet
granulation, AIChE J. (2016), http://dx.doi.org/10.1002/aic.15401.
[292] C. Garth, A. Middel, H. Hagen, CFD simulation of liquid–liquid extraction,
visualization of large and unstructured data sets: applications in geospatial
planning, modeling and engineering, in: IRTG 1131 Work., 2011.
[293] L. Fries, S. Antonyuk, S. Heinrich, S. Palzer, DEM–CFD modeling of a fluidized
bed spray granulator, Chem. Eng. Sci. 66 (2011) 2340–2355, http://dx.doi.org/
10.1016/j.ces.2011.02.038.
[294] M. Sen, D. Barrasso, R. Singh, R. Ramachandran, A multi-scale hybrid CFD-
DEM-PBM description of a fluid-bed granulation process, Processes 2 (2014)
89–111, http://dx.doi.org/10.3390/pr2010089.
[295] S.T.F.C. Mortier, T. De Beer, K.V. Gernaey, J.P. Remon, C. Vervaet, I. Nopens,
Mechanistic modelling of fluidized bed drying processes of wet porous
granules: a review, Eur. J. Pharm. Biopharm. 79 (2011) 205–225, http://dx.
doi.org/10.1016/j.ejpb.2011.05.013.
[296] A. Dubey, A. Sarkar, M. Ierapetritou, C.R. Wassgren, F.J. Muzzio,
Computational approaches for studying the granular dynamics of
continuous blending processes. 1 – DEM based methods, Macromol. Mater.
Eng. 296 (2011) 290–307, http://dx.doi.org/10.1002/mame.201000389.
[297] Y. Gao, F. Muzzio, M. Ierapetritou, Optimizing continuous powder mixing
processes using periodic section modeling, Chem. Eng. Sci. 80 (2012) 70–80.
http://www.sciencedirect.com/science/article/pii/S0009250912003181.
[298] A. Hassanpour, H. Tan, A. Bayly, P. Gopalkrishnan, B. Ng, M. Ghadiri, Analysis
of particle motion in a paddle mixer using Discrete Element Method (DEM),
Powder Technol. 206 (2011) 189–194, http://dx.doi.org/10.1016/j.
powtec.2010.07.025.
[299] D.J. Lucia, P.S. Beran, W.A. Silva, Reduced-order modeling: new approaches
for computational physics, Prog. Aerosp. Sci. 40 (2004) 51–117, http://dx.doi.
org/10.1016/j.paerosci.2003.12.001.
[300] A. Kumar, J. Vercruysse, S.T.F.C. Mortier, C. Vervaet, J.P. Remon, K.V. Gernaey,
T. De Beer, I. Nopens, Model-based analysis of a twin-screw wet
granulation system for continuous solid dosage manufacturing, Comput.
Chem. Eng. 89 (2016) 62–70, http://dx.doi.org/10.1016/j.compchemeng.
2016.03.007.
[301] D. Barrasso, S. Walia, R. Ramachandran, Multi-component population balance
modeling of continuous granulation processes: a parametric study and
comparison with experimental trends, Powder Technol. 241 (2013) 85–97,
http://dx.doi.org/10.1016/j.powtec.2013.03.001.
[302] T. Kulju, M. Paavola, H. Spittka, R.L. Keiski, E. Juuso, K. Leiviskä, E. Muurinen,
Modeling continuous high-shear wet granulation with DEM-PB, Chem. Eng.
Sci. 142 (2016) 190–200, http://dx.doi.org/10.1016/j.ces.2015.11.032.
[303] D. Barrasso, R. Ramachandran, A comparison of model order reduction
techniques for a four-dimensional population balance model describing
multi-component wet granulation processes, Chem. Eng. Sci. 80 (2012) 380–
392, http://dx.doi.org/10.1016/j.ces.2012.06.039.
[304] N. Hashemian, M. Ghanaatpishe, A. Armaou, Development of a reduced order
model for bi-component granulation processes via laguerre polynomials,
2016 Am. Control Conf IEEE, 2016, pp. 3668–3673, http://dx.doi.org/10.1109/
ACC.2016.7525483.
[305] M. Landin, Artificial intelligence tools for scaling up of high shear wet
granulation process, J. Pharm. Sci. 106 (2017) 273–277, http://dx.doi.org/
10.1016/j.xphs.2016.09.022.
[306] B.H. Ng, Y.L. Ding, M. Ghadiri, Modelling of dense and complex granular flow
in high shear mixer granulator—a CFD approach, Chem. Eng. Sci. 64 (2009)
3622–3632, http://dx.doi.org/10.1016/j.ces.2009.05.011.
[307] A. Darelius, A. Rasmuson, B. van Wachem, I. Niklasson Björn, S. Folestad, CFD
simulation of the high shear mixing process using kinetic theory of granular
flow and frictional stress models, Chem. Eng. Sci. 63 (2008) 2188–2197,
http://dx.doi.org/10.1016/j.ces.2008.01.018.
814 P. Suresh et al. / Chemical Engineering Journal 328 (2017) 785–815
[308] M. Adepu, S. Hate, A. Bétard, S. Oka, M. Schongut, M. Sen, Y. Sood, D. Wolf, S.
Wieland, F. Stepanek, F. Muzzio, B. Glasser, R. Ramachandran, Quantitative
validation and analysis of the regime map approach for the wet granulation
of industrially relevant zirconium hydroxide powders, Powder Technol. 294
(2016) 177–184, http://dx.doi.org/10.1016/j.powtec.2016.02.026.
[309] M. Hussain, J. Kumar, E. Tsotsas, Micro-macro transition of population
balances in fluidized bed granulation, Procedia Eng. 102 (2015) 1399–1407,
http://dx.doi.org/10.1016/j.proeng.2015.01.272.
[310] A. Chaudhury, H. Wu, M. Khan, R. Ramachandran, A mechanistic population
balance model for granulation processes: effect of process and formulation
parameters, Chem. Eng. Sci. 107 (2014) 76–92, http://dx.doi.org/10.1016/j.
ces.2013.11.031.
[311] P. Pandey, J. Tao, A. Chaudhury, R. Ramachandran, J.Z. Gao, D.S. Bindra, A
combined experimental and modeling approach to study the effects of high-
shear wet granulation process parameters on granule characteristics, Pharm.
Dev. Technol. 18 (2013) 210–224, http://dx.doi.org/10.3109/
10837450.2012.700933.
[312] A. Darelius, H. Brage, A. Rasmuson, I. Niklasson Björn, S. Folestad, A volume-
based multi-dimensional population balance approach for modelling high
shear granulation, Chem. Eng. Sci. 61 (2006) 2482–2493, http://dx.doi.org/
10.1016/j.ces.2005.11.016.
[313] P.K. Le, P. Avontuur, M.J. Hounslow, A.D. Salman, The kinetics of the
granulation process: right from the early stages, Powder Technol. 189
(2009) 149–157, http://dx.doi.org/10.1016/j.powtec.2008.04.018.
[314] A. Chaudhury, R. Ramachandran, Integrated population balance model
development and validation of a granulation process, Part. Sci. Technol. 31
(2013) 407–418, http://dx.doi.org/10.1080/02726351.2013.767295.
[315] A. Chaudhury, M.E. Armenante, R. Ramachandran, Compartment based
population balance modeling of a high shear wet granulation process using
data analytics, Chem. Eng. Res. Des. 95 (2015) 211–228, http://dx.doi.org/
10.1016/j.cherd.2014.10.024.
[316] D. Barrasso, A. Tamrakar, R. Ramachandran, Model order reduction of a multi-
scale PBM-DEM description of a wet granulation process via ANN, Procedia
Eng. 102 (2015) 1295–1304, http://dx.doi.org/10.1016/j.proeng.2015.01.260.
[317] B. Waldie, D. Wilkinson, L. Zachra, Kinetics and mechanisms of growth in
batch and continuous fluidized bed granulation, Chem. Eng. Sci. 42 (1987)
653–665, http://dx.doi.org/10.1016/0009-2509(87)80026-X.
[318] A. Heim, W. Antkowiak, A mathematical model for granulation kinetics,
Chem. Eng. Sci. 43 (1988) 1447–1456, http://dx.doi.org/10.1016/0009-2509
(88)85136-4.
[319] J. Kucharski, A. Kmieć, Kinetics of granulation process during coating of
tablets in a spouted bed, Chem. Eng. Sci. 44 (1989) 1627–1636, http://dx.doi.
org/10.1016/0009-2509(89)80005-3.
[320] P.C. Knight, An investigation of the kinetics of granulation using a high shear
mixer, Powder Technol. 77 (1993) 159–169, http://dx.doi.org/10.1016/0032-
5910(93)80053-D.
[321] T. Abberger, The effect of powder type, free moisture and deformation
behaviour of granules on the kinetics of fluid-bed granulation, Eur. J. Pharm.
Biopharm. 52 (2001) 327–336, http://dx.doi.org/10.1016/S0939-6411(01)
00185-0.
[322] H.S. Tan, A.D. Salman, M.J. Hounslow, Kinetics of fluidised bed melt
granulation I: the effect of process variables, Chem. Eng. Sci. 61 (2006)
1585–1601, http://dx.doi.org/10.1016/j.ces.2005.09.012.
[323] H.S. Tan, A.D. Salman, M.J. Hounslow, Kinetics of fluidized bed melt
granulation—II: modelling the net rate of growth, Chem. Eng. Sci. 61 (2006)
3930–3941, http://dx.doi.org/10.1016/j.ces.2006.01.005.
[324] H.S. Tan, A.D. Salman, M.J. Hounslow, Kinetics of fluidised bed melt
granulation III: tracer studies, Chem. Eng. Sci. 60 (2005) 3835–3845, http://
dx.doi.org/10.1016/j.ces.2005.02.009.
[325] A. Realpe, C. Velázquez, Growth kinetics and mechanism of wet granulation
in a laboratory-scale high shear mixer: effect of initial polydispersity of
particle size, Chem. Eng. Sci. 63 (2008) 1602–1611, http://dx.doi.org/
10.1016/j.ces.2007.11.018.
[326] S. Nalesso, C. Codemo, E. Franceschinis, N. Realdon, R. Artoni, A.C. Santomaso,
Texture analysis as a tool to study the kinetics of wet agglomeration
processes, Int. J. Pharm. 485 (2015) 61–69, http://dx.doi.org/10.1016/j.
ijpharm.2015.03.007.
[327] A.M. Bouwman, M.R. Visser, G.M.H. Meesters, H.W. Frijlink, The use of Stokes
deformation number as a predictive tool for material exchange behaviour of
granules in the ‘‘equilibrium phase” in high shear granulation, Int. J. Pharm.
318 (2006) 78–85, http://dx.doi.org/10.1016/j.ijpharm.2006.03.038.
[328] B.J. Ennis, G.I. Tardos, R. Pfeffer, A micro-level-based classification of
granulation regimes and mechanisms, in: Proc. Second World Congr.
Powder Technol., Kyoto, 1990, p. 409.
[329] K.P. Hapgood, J.D. Litster, S.R. Biggs, T. Howes, Drop penetration into porous
powder beds, J. Colloid Interface Sci. 253 (2002) 353–366, http://dx.doi.org/
10.1006/jcis.2002.8527.
[330] R. Johnstone, M. Thring, Pilot Plants Models and Scale up Methods in
Chemical Engineering, McGraw-Hill, New York, 1957.
[331] G.I. Tardos, K.P. Hapgood, O.O. Ipadeola, J.N. Michaels, Stress measurements
in high-shear granulators using calibrated ‘‘test” particles: application to
scale-up, Powder Technol. 140 (2004) 217–227, http://dx.doi.org/10.1016/j.
powtec.2004.01.015.
[332] T. Fitzgerald, S. Crane, Cold fluidizing bed modelling, Tech. Sess. 3 (1985) 85–
92.
[333] S. Watano, Y. Sato, K. Miyanami, T. Murakami, Y. Ito, T. Kamata, N. Oda, Scale-
up of agitation fluidized bed granulation. I. Preliminary experimental
approach for optimization of process variables, Chem. Pharm. Bull. (Tokyo)
43 (1995) 1212–1216, http://dx.doi.org/10.1248/cpb.43.1212.
[334] A. Hassanpour, C.C. Kwan, B.H. Ng, N. Rahmanian, Y.L. Ding, S.J. Antony, X.D.
Jia, M. Ghadiri, Effect of granulation scale-up on the strength of granules,
Powder Technol. 189 (2009) 304–312, http://dx.doi.org/10.1016/j.
powtec.2008.04.023.
[335] S. Watano, T. Okamoto, Y. Sato, Y. Osako, Scale-up of high shear granulation
based on the internal stress measurement, Chem. Pharm. Bull. (Tokyo) 53
(2005) 351–354, http://dx.doi.org/10.1248/cpb.53.351.
[336] G. Horsthuis, J. Vanlaarhoven, R. Vanrooij, H. Vromans, Studies on upscaling
parameters of the Gral high shear granulation process, Int. J. Pharm. 92
(1993) 143–150, http://dx.doi.org/10.1016/0378-5173(93)90273-I.
[337] D. Kayrak-Talay, S. Dale, C. Wassgren, J. Litster, Quality by design for wet
granulation in pharmaceutical processing: assessing models for a priori
design and scaling, Powder Technol. 240 (2013) 7–18, http://dx.doi.org/
10.1016/j.powtec.2012.07.013.
[338] Y. Sato, T. Okamoto, S. Watano, Scale-up of high shear granulation based on
agitation power, Chem. Pharm. Bull. (Tokyo) 53 (2005) 1547–1550, http://
www.ncbi.nlm.nih.gov/pubmed/16327186.
[339] S. Aikawa, N. Fujita, H. Myojo, T. Hayashi, T. Tanino, Scale-up studies on high
shear wet granulation process from mini-scale to commercial scale, Chem.
Pharm. Bull. (Tokyo) 56 (2008) 1431–1435, http://dx.doi.org/10.1248/
cpb.56.1431.
[340] A. Faure, P. York, R.C. Rowe, Process control and scale-up of pharmaceutical
wet granulation processes: a review, Eur. J. Pharm. Biopharm. 52 (2001) 269–
277, http://dx.doi.org/10.1016/S0939-6411(01)00184-9.
[341] G.A. Campbell, D.J. Clancy, J.X. Zhang, M.K. Gupta, C.K. Oh, Closing the gap in
series scale up of high shear wet granulation process using impeller power
and blade design, Powder Technol. 205 (2011) 184–192, http://dx.doi.org/
10.1016/j.powtec.2010.09.009.
[342] P. Pandey, S. Badawy, A quality by design approach to scale-up of high-shear
wet granulation process, Drug Dev. Ind. Pharm. 42 (2016) 175–189, http://dx.
doi.org/10.3109/03639045.2015.1100199.
[343] P. Holm, T. Schaefer, H.G. Kristensen, Granulation in high-speed mixers Part
V. Power consumption and temperature changes during granulation, Powder
Technol. 43 (1985) 213–223, http://dx.doi.org/10.1016/0032-5910(85)
80002-4.
[344] P. Holm, T. Schaefer, H.G. Kristensen, Granulation in high-speed mixers Part
VI. Effects of process conditions on power consumption and granule growth,
Powder Technol. 43 (1985) 225–233, http://dx.doi.org/10.1016/0032-5910
(85)80003-6.
[345] T. Schaefer, P. Holm, H.G. Kristensen, Wet granulation in a laboratory scale
high shear mixer https://www.scopus.com/record/display.uri?eid=2-s2.0-
0025147361&origin=resultslist&sort=plf-f&src=s&st1 = Wet+granulation+in+
a+laboratory+scale+high+shear+mixer&nlo=&nlr=&nls=&sid=570DA47946C
3FFDAD26822EFA52FDE07.wsnAw8kcdt7IPYLO0V48gA%3A27590&sot=b&
sdt=cl& Pharm. Ind. 52 (1990) 1147–1153.
[346] H. Leuenberger, Granulation, new techniques, Pharm. Acta Helv. 57 (1982)
72–82, http://www.ncbi.nlm.nih.gov/pubmed/7071070.
[347] N.O. Lindberg, Studies on granulation in a small planetary mixer. II.
Granulation of lactose and an antacid mixture, Acta Pharm. Suec. 14 (1977)
197–204, http://www.ncbi.nlm.nih.gov/pubmed/906837.
[348] L.S.C. Wan, K.P.P. Prasad, Tablet excipients and mixer energy consumption in
wet granulation https://www.scopus.com/record/display.uri?eid=2-s2.0-
0023698069&origin=resultslist&sort=plf-f&src=s&st1=Tablet+excipients+and
+mixer+energy+consumption+in+wet+granulation&st2=&sid=570DA47946C
3FFDAD26822EFA52FDE07.wsnAw8kcdt7IPYLO0V48gA%3A28060&sot=b&sd
t=b& Acta Pharm. Technol. 34 (1988) 200–203.
[349] J. Werani, Production experience with endpoint control, Acta Pharm. Suec. 25
(1988) 247–266.
[350] M. Ritala, O. Jungersen, P. Holm, T. Schæfer, H.G. Kristensen, A Comparison
Between Binders in the Wet Phase of Granulation in a High Shear Mixer, Drug
Dev. Ind. Pharm. 12 (1986) 1685–1700, http://dx.doi.org/10.3109/
03639048609042603.
[351] N.-O. Lindberg, C. Jönsson, Granulation of Lactose in a Recording High-Speed
Mixer, Diosna P25, Drug Dev. Ind. Pharm. 9 (1983) 959–970, http://dx.doi.
org/10.3109/03639048309042835.
[352] N.-O. Lindberg, L. Leander, B. Reenstierna, Instrumentation of a Kenwood
Major Domestic-Type Mixer for Studies of Granulation, Drug Dev. Ind. Pharm.
8 (1982) 775–782, http://dx.doi.org/10.3109/03639048209042702.
[353] H.G. Kristensen, P. Holm, T. Schaefer, Mechanical properties of moist
agglomerates in relation to granulation mechanisms part I, Deformability
of moist, densified agglomerates, Powder Technol. 44 (1985) 227–237, http://
dx.doi.org/10.1016/0032-5910(85)85004-X.
[354] M. Parker, R. Rowe, N. Upjohn, MIxer torque rheometry, A method for
quantifying the conssitency of wet granulations, Pharm Tech Int. 2 (1990)
50–64.
[355] M. Landín, R.C. Rowe, P. York, Characterization of Wet Powder Masses with a
Mixer Torque Rheometer. 3. Nonlinear Effects of Shaft Speed and Sample
Weight, J. Pharm. Sci. 84 (1995) 557–560, http://dx.doi.org/10.1002/
jps.2600840508.
[356] S.I.F. Badawy, M.M. Menning, M.A. Gorko, D.L. Gilbert, Effect of process
parameters on compressibility of granulation manufactured in a high-shear
 P. Suresh et al. / Chemical Engineering Journal 328 (2017) 785–815
mixer, Int. J. Pharm. 198 (2000) 51–61, http://dx.doi.org/10.1016/S0378-
5173(99)00445-7.
[357] P. Pandey, P.D. Sinko, D.S. Bindra, R. Hamey, S. Gour, C. Vema-Varapu,
Processing challenges with solid dosage formulations containing vitamin E
TPGS, Pharm. Dev. Technol. 18 (2013) 296–304, http://dx.doi.org/10.3109/
10837450.2012.737807.
[358] J. Tao, P. Pandey, D.S. Bindra, J.Z. Gao, A.S. Narang, Evaluating scale-up rules of
a high-shear wet granulation process, J. Pharm. Sci. 104 (2015) 2323–2333,
http://dx.doi.org/10.1002/jps.24504.
[359] B. Rambali, Scaling up of the fluidized bed granulation process, Int. J. Pharm.
252 (2003) 197–206, http://dx.doi.org/10.1016/S0378-5173(02)00646-4.
[360] T. Schaefer, O. Worts, Control of fluidized bed granulation. II. Estimation of
droplet size of atomized binder solutions, Arch. Pharm. Sci. Ed. 5 (1977) 178–
193.
[361] L. Juslin, Droplet size measurement: I. Effect of three independent variables
on droplet size distribution and spray angle from a pneumatic nozzle, Int. J.
Pharm. 123 (1995) 247–256, http://dx.doi.org/10.1016/0378-5173(95)
00081-S.
[362] T. Schaefer, O. Worts, Control of fluidized bed granulation I. Effects of spray
angle, nozzle height and starting materials on granule size and size
distribution, Arch. Pharm. Chem. Sci. Ed. 5 (1977) 51–60.
[363] J.D. Lister, S.M. Iveson, K.P. Hapgood, Predicting and controlling granule
properties in granulation processes, World Congr. Part. Technol., The
Institution of Chemical Engineers, Brighton, 1998.
[364] M. Horio, A. Nonaka, Y. Sawa, I. Muchi, A new similarity rule for fluidized bed
scale-up, AIChE J. 32 (1986) 1466–1482, http://dx.doi.org/10.1002/
aic.690320908.
[365] G.I. Tardos, Wet-granulation research with application to scale-up, China
Particuology. 3 (2005) 191–195, http://dx.doi.org/10.1016/S1672-2515(07)
60085-2.
[366] K. Giry, M. Viana, M. Genty, P. Wüthrich, D. Chulia, Switch from single pot to
multiphase high shear wet granulation process, influence of the volume of
granulation liquid in a pilot scale study, Chem. Eng. Process. Process Intensif.
48 (2009) 1293–1301, http://dx.doi.org/10.1016/j.cep.2009.05.008.
[367] J.W. Kwek, M.W. Lim, S.C. Shen, W.K. Ng, R.B.H. Tan, A pilot scale study on the
fluidized bed binderless granulation of a humidified type C hygroscopic
pharmaceutical material, Powder Technol. 219 (2012) 65–71, http://dx.doi.
org/10.1016/j.powtec.2011.12.010.
[368] I.M. Cotabarren, D.E. Bertín, V. Bucalá, J. Piña, Feedback control strategies for a
continuous industrial fluidized-bed granulation process, Powder Technol.
283 (2015) 415–432, http://dx.doi.org/10.1016/j.powtec.2015.06.010.
[369] M. Horio, M. Ishida, M. Takada, N. Tanaka, he similarity rule of fluidization
and its application to solid mixing and circulation control, Proc Fluidization V
Engineering Foundation, New York, 1986, https://www.scopus.com/
record/display.uri?eid=2-s2.0-0022493163&origin=resultslist&sort=plf-
f&src=s& st1=1The+similarity+rule+of+fluidization+and+its+application
+to+solid+mixing+and+circulation+control&st2 =&sid =570DA47946C3F
FDAD26822EF A52FDE07.wsnAw8kcdt7IP.
[370] T. Chirkot, Scale-up and endpoint issues of pharmaceutical wet granulation in
a V-type low shear granulator, Drug Dev. Ind. Pharm. 28 (2002) 871–888,
http://dx.doi.org/10.1081/DDC-120005633.
[371] P. Holm, T. Schaefer, C. Larsen, End-point detection in a wet granulation
process, Pharm. Dev. Technol. 6 (2001) 181–192, http://dx.doi.org/10.1081/
PDT-100000739.
[372] S.P. Chaudhari, R.H. Dave, To prepare and characterize microcrystalline
cellulose granules using water and isopropyl alcohol as granulating agents
and determine its end-point by thermal and rheological tools, Drug Dev. Ind.
Pharm. 41 (2015) 744–752, http://dx.doi.org/10.3109/03639045.2014.
900080.
[373] A.S. Narang, T. Stevens, K. Macias, S. Paruchuri, Z. Gao, S. Badawy, Application
of in-line focused beam reflectance measurement to brivanib alaninate wet
granulation process to enable scale-up and attribute-based monitoring and
control strategies, J. Pharm. Sci. 106 (2017) 224–233, http://dx.doi.org/
10.1016/j.xphs.2016.08.025.
[374] M. Otsuka, Y. Mouri, Y. Matsuda, Chemometric evaluation of pharmaceutical
properties of antipyrine granules by near-infrared spectroscopy, AAPS
PharmSciTech. 4 (2003) 142–148, http://dx.doi.org/10.1208/pt040347.
[375] J.F. Gamble, A.B. Dennis, M. Tobyn, Monitoring and end-point prediction of a
small scale wet granulation process using acoustic emission, Pharm. Dev.
Technol. 14 (2009) 299–304, http://dx.doi.org/10.1080/10837450802603618.
[376] B.M. Zacour, J.K. Drennen, C.A. Anderson, Hybrid controls combining first-
principle calculations with empirical modeling for fully automated fluid bed
processing, J. Pharm. Innov. 7 (2012) 140–150, http://dx.doi.org/10.1007/
s12247-012-9137-7.
815
[377] R.H. Dave, S.H. Wu, L.D. Contractor, To determine the end point of wet
granulation by measuring powder energies and thermal properties, Drug
Dev. Ind. Pharm. 38 (2012) 439–446, http://dx.doi.org/10.3109/
03639045.2011.609561.
[378] Z. Arp, B. Smith, E. Dycus, D. O’grady, Optimization of a high shear wet
granulation process using focused beam reflectance measurement and
particle vision microscope technologies, J. Pharm. Sci. 100 (2011) 3431–
3440, http://dx.doi.org/10.1002/jps.22556.
[379] A. Burggraeve, A.F.T. Silva, T. Van den Kerkhof, M. Hellings, C. Vervaet, J.P.
Remon, Y. Vander Heyden, T. De Beer, Development of a fluid bed granulation
process control strategy based on real-time process and product
measurements, Talanta. 100 (2012) 293–302, http://dx.doi.org/10.1016/
j.talanta.2012.07.054.
[380] C.F.W. Sanders, M.J. Hounslow, F.J. Doyle, Identification of models for control
of wet granulation, Powder Technol. 188 (2009) 255–263, http://dx.doi.org/
10.1016/j.powtec.2008.05.005.
[381] C.E. Long, P.K. Polisetty, E.P. Gatzke, Deterministic global optimization for
nonlinear model predictive control of hybrid dynamic systems, Int. J. Robust
Nonlinear Control. 17 (2007) 1232–1250, http://dx.doi.org/10.1002/rnc.1105.
[382] M. Pottmann, B.A. Ogunnaike, A.A. Adetayo, B.J. Ennis, Model-based control of
a granulation system, Powder Technol. 108 (2000) 192–201, http://dx.doi.
org/10.1016/S0032-5910(99)00220-X.
[383] F. Boukouvala, A. Chaudhury, M. Sen, R. Zhou, L. Mioduszewski, M.G.
Ierapetritou, R. Ramachandran, Computer-aided flowsheet simulation of a
pharmaceutical tablet manufacturing process incorporating wet granulation,
J. Pharm. Innov. 8 (2013) 11–27, http://dx.doi.org/10.1007/s12247-012-
9143-9.
[384] R. Singh, D. Barrasso, A. Chaudhury, M. Sen, M. Ierapetritou, R.
Ramachandran, Closed-loop feedback control of a continuous
pharmaceutical tablet manufacturing process via wet granulation, J. Pharm.
Innov. 9 (2014) 16–37, http://dx.doi.org/10.1007/s12247-014-9170-9.
[385] A. Khadilkar, P.L. Rozelle, S.V. Pisupati, Models of agglomerate growth in
fluidized bed reactors: critical review, status and applications, Powder
Technol. 264 (2014) 216–228, http://dx.doi.org/10.1016/j.
powtec.2014.04.063.
[386] J. Petrović, K. Chansanroj, B. Meier, S. Ibrić, G. Betz, Analysis of fluidized bed
granulation process using conventional and novel modeling techniques, Eur.
J. Pharm. Sci. 44 (2011) 227–234, http://dx.doi.org/10.1016/j.
ejps.2011.07.013.
[387] R.M. Dhenge, R.S. Fyles, J.J. Cartwright, D.G. Doughty, M.J. Hounslow, A.D.
Salman, Twin screw wet granulation: granule properties, Chem. Eng. J. 164
(2010) 322–329, http://dx.doi.org/10.1016/j.cej.2010.05.023.
[388] S.I.F. Badawy, A.S. Narang, K. LaMarche, G. Subramanian, S.A. Varia,
Mechanistic basis for the effects of process parameters on quality
attributes in high shear wet granulation, Int. J. Pharm. 439 (2012) 324–333,
http://dx.doi.org/10.1016/j.ijpharm.2012.09.011.
[389] L. Briens, R. Logan, The effect of the chopper on granules from wet high-shear
granulation using a PMA-1 granulator, AAPS PharmSciTech. 12 (2011) 1358–
1365, http://dx.doi.org/10.1208/s12249-011-9703-1.
[390] S. Wang, G. Ye, P.W.S. Heng, M. Ma, Investigation of high shear wet
granulation processes using different parameters and formulations, Chem.
Pharm. Bull. (Tokyo) 56 (2008) 22–27, http://dx.doi.org/10.1248/cpb.56.22.
[391] T.M. Chitu, D. Oulahna, M. Hemati, Wet granulation in laboratory-scale high
shear mixers: effect of chopper presence, design and impeller speed, Powder
Technol. 206 (2011) 34–43, http://dx.doi.org/10.1016/j.powtec.2010.07.016.
[392] M. Hemati, R. Cherif, K. Saleh, V. Pont, Fluidized bed coating and granulation:
influence of process-related variables and physicochemical properties on the
growth kinetics, Powder Technol. 130 (2003) 18–34, http://dx.doi.org/
10.1016/S0032-5910(02)00221-8.
[393] P.G. Smith, A.W. Nienow, Particle growth mechanisms in fluidised bed
granulation—I, Chem. Eng. Sci. 38 (1983) 1223–1231, http://dx.doi.org/
10.1016/0009-2509(83)80042-6.
[394] M.F. Saleh, R.M. Dhenge, J.J. Cartwright, M.J. Hounslow, A.D. Salman, Twin
screw wet granulation: binder delivery, Int. J. Pharm. 487 (2015) 124–134,
http://dx.doi.org/10.1016/j.ijpharm.2015.04.017.
[395] R.M. Dhenge, J.J. Cartwright, D.G. Doughty, M.J. Hounslow, A.D. Salman, Twin
screw wet granulation: effect of powder feed rate, Adv. Powder Technol. 22
(2011) 162–166, http://dx.doi.org/10.1016/j.apt.2010.09.004.
[396] M.F. Saleh, R.M. Dhenge, J.J. Cartwright, M.J. Hounslow, A.D. Salman, Twin
screw wet granulation: effect of process and formulation variables on
powder caking during production, Int. J. Pharm. 496 (2015) 571–582, http://
dx.doi.org/10.1016/j.ijpharm.2015.10.069.