1. Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=iddi20
Download by: [LIU Libraries] Date: 16 May 2016, At: 12:55
Drug Development and Industrial Pharmacy
ISSN: 0363-9045 (Print) 1520-5762 (Online) Journal homepage: http://www.tandfonline.com/loi/iddi20
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
Smruti P. Chaudhari & Rutesh H. Dave
To cite this article: Smruti P. Chaudhari & Rutesh H. Dave (2015) 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 Development and Industrial
Pharmacy, 41:5, 744-752, DOI: 10.3109/03639045.2014.900080
To link to this article: http://dx.doi.org/10.3109/03639045.2014.900080
Published online: 24 Mar 2014.
Submit your article to this journal
Article views: 63
View related articles
View Crossmark data

2. http://informahealthcare.com/ddi
ISSN: 0363-9045 (print), 1520-5762 (electronic)
Drug Dev Ind Pharm, 2015; 41(5): 744–752
! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/03639045.2014.900080
RESEARCH ARTICLE
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
Smruti P. Chaudhari and Rutesh H. Dave
Division of Pharmaceutical Sciences, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY, USA
Abstract
Microcrystalline cellulose (MCC-102) is one of the most commonly used excipient in the
pharmaceutical industry. For this research purpose, authors have developed a different
technique to determine the end point for MCC-102 using water and isopropyl alcohol 70% (IPA)
as granulating agent. Wet and dry granules obtained were characterized for their flow
properties using the powder rheometer and thermal analysis. Powder rheometer was used to
measure basic flowability energy (BFE), specific energy (SE), percentage compressibility,
permeability and aeration. Thermal analysis includes effusivity and differential scanning
calorimetry (DSC) measurements. BFE and SE results showed water granules requires high
energy as compared to IPA granules. Permeability and compressibility results suggest IPA forms
more porous granules and have better compressibility as compared to water granules.
Hardness data reveals interesting phenomena in which as the amount of water increases,
hardness decreases and vice-versa for IPA. Optimal granules were obtained in the range of
45–55% w/w. DSC data supported the formation of optimal granules. Empirical measurements
like angle of repose did not reveal any significant differences between powder flow among
various granules. In this paper, with the help of thermal effusivity and powder rheology we
were able to differentiate between various powder flows and determine the optimal range for
granule formation.
Keywords
Effusivity, end point determination,
granulation, microcrystalline cellulose,
powder rheometer
History
Received 2 December 2013
Revised 24 February 2014
Accepted 26 February 2014
Published online 26 March 2014
Introduction
Oral drug delivery systems (ODDS) are the most convenient
dosage forms available in the market. Despite many years of
research, content uniformity and weight variation still remain as a
major issue in ODDS. These issues can be attributed to poor flow
of powder from hopper to the die or segregation of the powders in
the hopper, which creates the need to understand powder
behavior.
There are several ways to address these issues and the most
common is to redesign the hopper using a recommended hopper
angle, the use of force feeders or addition of flowing agents. Wet
granulation is also one of the most commonly used techniques.
There are two types of granulations: wet granulation and dry
granulation. Dry granulation is preferred due to its cost effect-
iveness and ease of manufacturing. However, the granules formed
using the dry granulation process are more dense and irregular
than the original powder, since the material is densified under
pressure and milled to obtain granules1
. Conversely, granules
formed by wet granulation are voluminous and show better
compressibility and compactibility as compared to granules
formed by dry granulation2
. The wet granulation process has
three most important steps: solvent selection, optimization of the
mixing time and determination of end point. In this paper, we
have used a wet granulation process for granulation and charac-
terization of microcrystalline cellulose -102 (MCC-102) using
water and isopropyl alcohol 70% (IPA) using powder rheometer.
MCC-102 is the most commonly used filler in the tableting
industry. The tablet compact formed using MCC-102, when
exposed to humid conditions tends to swell and soften but regains
its original properties on the removal of excess moisture; however,
it has been reported that even after water removal, there is still
change in enthalpy of water sorption which again is responsible
for change in the internal bonding within the cellulose structure
upon wet granulation and drying3
. MCC-102 also shows fast
disintegration in high-polarity solvents, since hydrogen bonding is
largely responsible for holding individual crystallites of MCC in
tablet compacts4
. It has also been reported that water wet
granulated MCC-102 shows the loss of binding ability during
tableting, swelling and disintegration, due to irreversible hydro-
gen bonding and densification during drying5
. Change in
hydrogen bonding can also be expected after wet granulation
using water as solvent of choice6
. However, X-ray diffraction,
Address for correspondence: Rutesh H. Dave, Division of Pharmaceutical
Sciences, Arnold & Marie Schwartz College of Pharmacy and
Health Sciences, Long Island University, Brooklyn, NY 11201, USA.
Tel: +718-488-1660. Fax: +718-780-4586. E-mail: rutesh.dave@liu.edu
Downloadedby[LIULibraries]at12:5516May2016

3. magnetic angle spinning nuclear magnetic resonance, degree of
crystallinity and oxygen combustion calorimetry, fail to provide
evidence for significant change in hydrogen bonding7
. High
porosity pellets were formed when water–ethanol or water–
isopropyl alcohol was used as compared to water alone7
.
Granulating fluid influences mechanical and structural properties
of pellets by governing contraction driving and contraction
counteracting forces during drying8
. Porosity of MCC pellets
depends on the drying method, hence drying methods like freeze
drying which allows minimal capillary flow gives pellets of
highest porosity as compared to conventional drying methods
when using water as a granulating fluid9
.
Mixing time is one critical step involved in wet granulation.
Optimum mixing time is required to attain equilibrium granule
size. Excessive mixing changes the packaging arrangement of
granules due to dissolving of excess material during drying,
causing granules to become non-porous and dense10
. In this
research, we have utilized thermal effusivity measurement
technique to optimize mixing time. It can also be used as the
indicator of mixing time efficiency as it depends on the heat
capacity, thermal conductivity and density of the material11–13
.
Another critical step in wet granulation is end-point determin-
ation. It is of utmost importance since over-granulated powders
often result in larger granules with lower tablet ability. Large
granules have lower intragranular bonding which causes granules
to become hard and resistant to grinding14
. It has also been shown,
that flowability is improved as we lower the particle size.
However, if the particle size is reduced below a certain limit the
opposite effect can be observed due to dominant interparticulate
forces such as vander Waals’ forces and electrostatic forces.
Optimum particle size range is required for good flowability.
MCC shows segregation issues with broad particle size distribu-
tion which in turn result in weight variation and content
uniformity issues15
.
Over recent years a few methods have developed for end-point
determination. The most commonly used is to measure power
consumption in high shear granulator. A linear correlation was
found between mean granule size and power consumption. This
approach is limited to impellar design, impellar speed, liquid
addition rate and type of binder16
. Some scientists have
determined end-point based on a mathematical model, where
the amount of water needed for each excipient was determined
with the help of a refractive near-infrared moisture sensor
which measures the moisture at the surface of the powder.
Summation of water need to all excipients gives the water
needed for tablet formulation17
. Near infra-red spectroscopy18,19
,
acoustic emission20
, and the application of artificial neural
networks21
are some methods used to characterize powder flow
and determination of end points. However, these methods lack
reproducibility.
Granule flowability can be measured with the help of a
rheometer. Previously, it has reported that powder flow properties
can be characterized by powder rheometer22
. Researchers have
used mixer torque rheometer to determine the relationship
between dried granules and wet mass consistency. It is proved
that wet mass with good consistency produces granules with good
flow property23
. The addition of water to MCC changes thermal
properties of MCC like glass transition temperature (Tg) which
suggests that isopropyl alcohol does not have any significant
change in Tg24
.
In this study, we have used a powder rheometer to determine
powder flowability of wet mass as well as dried granules formed
by using water and isopropyl alcohol as granulating agents. We
used effusivity measurements and thermal analysis to support our
data. This information will provide a unique way to identify the
end point of wet granulation and give importance to various
energies involved in powders and finally comparison using two
different granulating agents.
Materials and methods
Material
Microcrystalline Cellulose (MCC, AvicelÕ
102) was generously
donated by FMC Biopolymer, Newark, DE (Lot# P209821062),
deionized water was obtained using Barnstead Nanopure system
below 13 mV-cm (Thermoscientific system, Waltham, MA) and
iso-propyl alcohol was obtained from VWR, Westchester, PA (lot
no. 110308B).
Preparation of granules (wet and dried)
Wet granules were prepared using a Cuisinart mixer (East
Windsor, NJ). Seven hundred grams of MCC-102 were granulated
using purified water and IPA. Granulating liquid was added
within 30 s while mixing at 15 rpm. Granulating liquids were
added to make the final concentration of water/IPA mixture 35,
45, 50, 55 and 60% w/w. After the addition of granulating liquid,
it was further mixed for an additional 3 min at 70 rpm.
Approximately 250 g of wet mass were collected and subjected
to a powder rheological and thermal analysis. The remaining wet
mass was passed through sieve #12 and dried in an oven at 60
C
until constant loss on drying (LOD) of 3% was obtained. Dried
samples were further passed through sieve #30 and subjected to
powder rheological measurements.
Powder rheological measurements
Powder rheological measurements were carried out using an FT-4
rheometer (Freeman Technology, Worcestershire, UK). These
characterizations include measurement of basic flowability energy
(BFE), specific energy (SE), compressibility, permeability and
aeration ratio (AR). The rheometer was initially calibrated for
force, torque and height measurements. All tests are performed
using 48 mm diameter helical blade in a 50 mm vessel. All
samples were initially subjected to conditioning by moving the
blade slowly in upward and downward while rotating clockwise.
Basic flowability energy measurements
This test was performed using a 50 mm  160 ml split vessel
assembly, fitted with a base and rested on an FT-4 platform using
a 48 mm blade. BFE is the energy required by the blade to move
down the blade through the powder bed at 100 mm tip speed and
À5
helix angle. Powder is forced to flow on the face of the blade.
Wet mass and dried granules were subjected to BFE measure-
ments. Two kinds of forces act on the blade, rotational force and
the axial force.
BFE is calculated using Equation (1):
Energy consumed : dE ¼ T=ðR tan Þ þ Fð ÞdH ð1Þ
where R ¼ blade radius; L ¼ vertical distance moved during one
complete revolution; ¼ helical path angle; F ¼ axial force on the
blade, in Newtons (N); T ¼ torque acting on blade (Nm).
Specific energy measurement
Specific energy is the energy required by the blade to move from
the bottom to the top of the vessel. This test was performed using
a 50 Â 160 ml assembly fitted with a solid base and rested on
the platform and a 48 mm diameter helical blade was used for
energy measurements. Energy is calculated as work done in
upward traverse movement of the blade from the bottom of the
powder blade.
DOI: 10.3109/03639045.2014.900080 End point determination 745
Downloadedby[LIULibraries]at12:5516May2016

4. Pressure drop measurements
This test was performed on wet and dried powders using
50 Â 85 ml assembly fitted with an aerated base and a vented
piston was used to compress the powder. Powders were
compressed at 1, 2, 4, 6, 8, 10, 12 and 15 kp, respectively, and
a constant air velocity of 2 mm/s was maintained throughout the
experiment. Data generated using this experiment did not show
significant change in permeability readings at different compres-
sion pressure and henceforth, 15 kp was selected as the compres-
sion pressure for wet mass and dried powders. Pressure drop (PD)
can be measured using the following equation:
k ¼ qL=DP ð2Þ
where k ¼ permeability (cm2
); ¼ air viscosity (Pa s)
(1.74 Â 10À5
Pa s); q ¼ air flow rate (cm/s); L ¼ length of the
powder bed (cm); DP ¼ pressure drop across the powder bed
(mbar).
Aeration ratio measurements
Aeration ratio (AR) measurements were carried out using a
48 mm blade and 50 mm  260 ml vessel fitted with an aeration
base. Variable amount of air is introduced from bottom of the
vessel, starting from 2 mm/s, followed by increase in increments
of 2 mm/s till it reaches 10 mm/s. AR is calculated using Equation
(3), where N ¼ 10 mm/s.
Aeration ratio ¼
Energy Airvelocity 0ð Þ
Energy Airvelocity nð Þ
ð3Þ
This test is performed only on the dried granules.
Compressibility
Compressibility is expressed as the percentage change in volume
after compression. This test is carried out in a 50 Â 85 ml vessel
fitted with a solid base and compressed using a vented piston.
In this test, powder is compressed at 15 kp. Change in volume is
noted at each compression pressure.
% Compressibility ¼ Percentage change in volume
after compression %ð Þ
ð4Þ
Tablet compression
Prepared granules were compressed into a 500 mg tablet using an
Enerpac single compression machine (GlobePharma, New
Brunswick, NJ) at 1500 psi, 2000 psi and 2500 psi. Round flat
faced punches (13 mm diameter) were used to compress tablets.
Hardness was measured using a Schleuniger tablet tester 6D
(Schleuniger Pharmatron Inc, Manchester, NH).
Sieve analysis
Sieve analysis was carried out using a sieve shaker Octagon 200
(Endecotts, UK). 100 g of powder were passed through sieves
stacked in ascending # 12, 14, 18, 20, 30 and 60. Sieves were
fitted on a collecting pan at the bottom. Sieves were subjected to
vibration for 5 min. Sieves were weighed before and after the test
and the mass retained on the sieve was calculated by the
difference in the initial and final sieve weight.
Angle of repose
A plastic funnel was fixed from a horizontal surface (glass plate)
and powder was placed in the plastic funnel and allowed to flow
under gravity. The height of the pile was kept 1.5 cm and radius
was measured. The angle of repose (AOR) was calculated by
Equation (5):
tan ¼
h
r
ð5Þ
where, h ¼ height of the pile of the powder; r ¼ radius of the pile
of the powder; y ¼ angle of repose.
Thermal measurements
Differential scanning calorimetry (DSC) and thermal effusivity
were used to perform thermal analysis.
Differential scanning calorimetry
The wet granules obtained were weighed approximately 5–15 mg
and placed in hermetically sealed aluminum pans, and measure-
ments were performed using Q100 (TA Instruments, New Castle,
DE) instrument with nitrogen (50 ml/min) as purge gas.
Samples were heated from 40 to 200
C at a constant heating
rate of 10
C/min. DSC was calibrated using indium before
starting the experiments.
Thermal effusivity measurements
Wet and dried granules were subjected to effusivity measurements
using a TC Probe (Mathis Instruments, New Brunswick, Canada).
The TC Probe sensor was inverted and placed in contact with the
granules. This instrument detects the heat flow and effusivity is
calculated using Equation (6):
¼
ffiffiffiffiffiffiffiffiffiffiffiffi
KCp
p
ð6Þ
where, ¼ effusivity; K ¼ thermal conductivity (W/m K); ¼
density (kg/m2
); Cp ¼ heat capacity (J/kg K).
Effusivity was used to optimize mixing time. For this
experiment, 700 g of MCC-102 were granulated with 45% w/w
of water and IPA, respectively. Samples were mixed at 70 rpm
after the addition of granulating fluid for 30 s, and samples were
taken at 1, 2, 3, 7 and 10 min after mixing and effusivity was
measured at each time point.
Effusivity was also used to determine end-point determination
for lab scale (7 g) and feasibility experiments (700 g). For lab
scale, 20, 30, 35, 40, 45, 50, 55, 60 and 70% w/w of granulating
agent was used. However, in case of feasibility studies, 35, 45, 50,
55 and 60% w/w of granulating agent was used. A detailed
explanation is given in ‘‘Results and discussion’’ section. After
addition and mixing of the granulating agent, 2–3 g of samples
were collected and subjected to effusivity measurements.
Results and discussion
Rheological measurements
Conditioning of the powders
In a powder rheometer, the packing of the powder is of utmost
importance. Powder, which is filled gently, will behave differently
from powder, which is consolidated, due to air entrapped in it.
Therefore, the conditioning of powders is carried out before
performing any tests, to remove compaction due to the loading of
a cell and to remove residual compaction from previous tests on
the powder25
. In a conditioning cycle, the blade moves in
downward direction followed by a move upwards in clockwise
direction, as shown in Figure 1. Typically a conditioning cycle
does not induce any compaction on powder; hence, a positive
helix angel is created in the downward movement of the blade,
which creates a slicing action to remove stress and excess air. This
results in a low stress packaging state. On other hand, a negative
746 S. P. Chaudhari R. H. Dave Drug Dev Ind Pharm, 2015; 41(5): 744–752
Downloadedby[LIULibraries]at12:5516May2016

5. helix angle is created during upward movement of the blade,
which gently lifts the powder and drops it over the blade to result
in particles falling from the blade and creating a properly packed
powder bed26
.
Characterization of BFE and SE related to wet and dried granules
Basic flowability energy depends on several physical properties of
powders such as particle size distribution, shape, texture, stiffness,
cohesivity, density, electrostatic charge, moisture content, elasti-
city, porosity, friability and surface additives. The interaction of
these powder properties will influence BFE measurements. BFE
is the measure of energy required to produce flow during a
downward traverse anticlockwise motion of the blade into the
powder to generate a high stress environment similar to those in
feeders. Compacting motion is generated due to the anticlockwise
downward direction of the blade. Since the powder is forced to
flow due to blade movement, many factors like attrition agglom-
eration, segregation and de-aeration plays a pivotal role.
In our case, as the granulating fluid is added in incremental
percentages, BFE increases. This phenomenon is due to decrease
in air pockets in-between wet granules as seen in Figure 2(a). The
energy required by the blade is increased due to high inter-particle
friction and high contact stresses throughout the flow zone. In a
wet mass the blade will require high energy, due to the cohesive
nature of the wet mass. As seen from Figure 2(a), there is
continuous rise in BFE until 55% of granulating fluid is added,
after which a sudden drop is observed in BFE. MCC-102 forms
highly cohesive mass after 55% of water addition, large amount of
air is entrapped in agglomerate. At this point, inter-particulate
forces are high as compared to gravitational force acting on the
particle. When particles are forced to flow at the blade face, air
pockets inside the agglomerate can accommodate the particle,
which results in low BFE values due to localized stress
transmission zone. In the case of IPA, MCC-102 forms slurry
after 55% of IPA addition, which results in the low BFE value.
Dried granules BFE which are obtained after the addition of
increasing granulating fluid are shown in Figure 2(b). Initially
after the addition of 35% granulating fluid, the BFE decreases as
compared to MCC-102 alone, followed by rise in BFE values. In
the case of IPA granules, they require less energy as compared to
water granules which implies the IPA granules are better flowing.
This phenomenon is due to hydrogen bonding in water gran-
ules3,27
, which tends to hold the granules tightly. It can also be
due to the strength of hydrogen bond being stronger in water as
compared to alcohol7
.
SE measures the powder flow in unconfined low stress
environments. It correlates with powder flow when being fed
gravimetrically. This process is analogous to die filling process.
It measures the flow of powders under gravity; hence, cohesion
forces between particles play an important role. Particle size,
texture, shear force and shape can also be the contribution factors.
Generally, the higher the SE values, higher the cohesion. As
the amount of water increases, MCC-102 forms a cohesive mass
which results in higher SE values as shown in Figure 3(a). SE
increases as the amount of IPA increases until 55% addition of
liquid. After this point, a sudden drop is observed in SE at 60%
addition of IPA due to the formation of slurry. It also reduces the
energy required by the blade, resulting in low SE values. Dried
granules formed after the addition of water (45%) show decrease
in SE values, above which, increases in SE values are observed as
seen in Figure 3(b). It suggests that cohesive forces are increased
as the amount of water increases. However, dried IPA granules
shows decrease in SE until they reach equilibrium at 45%;
after 45%, IPA granules show minimal change in SE as seen in
Figure 3(b). It should be noted that MCC-102 is a good flowing
powder by itself, however, the addition of water and IPA changes
the properties of the granules as expected. In the case of water, as
mentioned above, SE values increase as the percentage of water
addition increases and the opposite phenomena is observed in
case of IPA. This is due to the bonds formed in water are stronger
as compared to the ones which are formed using IPA.
Figure 2. BFE as a function of increasing granulating fluid.
Figure 1. Conditioning mode of blade.
DOI: 10.3109/03639045.2014.900080 End point determination 747
Downloadedby[LIULibraries]at12:5516May2016

6. Pressure drop
Pressure drop (PD) is the measure of permeability of the powders.
Permeability is influenced by many physical properties like
particle size distribution, cohesivity, particle stiffness, shape,
surface texture and bulk density. This test is helpful in
understanding the effect of permeability on many process
environments like pneumatic transfers, storage in and out of the
hoppers, vacuum transfer, vial filling or dry dose inhalation.
Permeability increases as the PD decreases (Equation (2)).
The PD of the 35, 45, 50, 55 and 60% w/w of granulating fluid
was measured as 2.56, 1.68, 0.90, 0.499 and 1.19 mbar,
respectively. It is evident, the PD decreases until 55%, beyond
that the PD starts to increase (Figure 4a). IPA shows decrease in
PD until 50%, and after that it starts to increase. In this test, the
powder bed is compressed using vented piston and the air is
supplied from below at 2 mm/s and the difference in pressure
gives us the PD. The compact mass formed by IPA does not allow
air to permeate through it resulting in large pressure difference
after 45% and the PD increase. Dried granules prepared from
both water and IPA showed a decrease in PD as granulating
fluid increased as seen in Figure 4(b). PD for the IPA granules
is less as compared to dried water granules; permeability of the
IPA granules is more than water granules. This result is in
agreement with the previous study carried on water/ethanol
mixtures27
.
Aeration ratio
The aeration test measures how easily powders get fluidized from
bulk powders. Some powder easily gets aerated, while some
requires sufficient amount of air to get fluidized. There are two
kinds of forces acting on the particle in the powder: cohesion
forces between the particles and forces acting due to gravity on
the particles. For a good flowing powder, restraining forces acting
on neighboring particles are sufficiently less as compared to
gravitational forces. Hence, AR is affected most by the cohesion
forces acting between the particles although some other physical
properties of the powders, like particle shape, texture and density,
can also play an important role.
Air supplied from the bottom in this test will reduce the energy
required by the blade to produce flow. Hence, the energy required
to produce powder flow will keep on decreasing as air velocity
increases. AR is calculated using Equation (3). Granules with
good flowability will easily get fluidized and energy required at
highest air velocity (10 mm/s) will be lower, resulting in higher
AR values, compared to granules with poor flow. As granulating
fluid increases, dried water granules and IPA granules show a
decrease in AR (Figure 5). However, the IPA shows higher AR as
compared to the water. IPA granules formed are easily fluidized as
compared to granules formed using water, suggesting that water-
formed granules have more cohesive forces than IPA-formed
granules.
Figure 3. SE as a function of increasing granulating fluid.
Figure 4. Pressure drop as a function of increasing granulating fluid.
748 S. P. Chaudhari R. H. Dave Drug Dev Ind Pharm, 2015; 41(5): 744–752
Downloadedby[LIULibraries]at12:5516May2016

7. Compressibility
Compressibility measures percentage change in volume after
compression. Here compression pressure of 15 kp was applied to
the powder bed. It measures the volume change of the powder bed
from initial state to final state, and % compressibility is calculated
from Equation (4). As the amount of water increases, the %
compressibility of the granules increases until 45% of water
addition, followed by a decrease in % compressibility until 55%,
seen in Figure 9. This is due to formation of cohesive mass after
55% addition of water. As we form cohesive wet mass there is
more air entrapped in it resulting in these phenomena. Granules
formed after the addition of IPA shows increase in % compress-
ibility values till 45% followed by plateau till 55% (Figure 6a).
After the addition of 55% IPA, it shows a decrease in compress-
ibility values due to slurry formation. In the case of dried granules
obtained by water, granulation shows continuous decreases in
compressibility seen in Figure 6(b). However, dried granules
formed by using IPA shows initial decrease at 35%, after which it
remains fairly constant. Water forms hard and strong granules,
which are difficult to compress and are resistant to grinding. This
may be the cause of the decrease in compressibility values.
Hardness measurement
In order to verify compressibility and compactibility, properties of
the granules hardness measurements were performed. Tablets
were compressed at 1500, 2000 and 2500 psi and data is shown in
Figure 7. It is seen that water forms granules with good shape but
they tend to be hard. As a result, more compaction energy is
utilized in breaking primary granule structure28
. In comparison to
tablets obtained using IPA as a granulating agent, hardness
increases as the percentage of IPA increases. This shows that
water granules are hard and are resistant to grinding and hence it
shows very less compressibility properties.
Water has previously been shown to have irreversible hydrogen
bonding4
. Scientists have also hypothesized that these difference
in strength are due to conversion of some of the intramolecular
hydrogen bonded amorphous fibrils at the surface of the MCC
particles to intermolecular hydrogen bonded fibrils with other
MCC particles5
. It has also been shown that the change in strength
can also be due to internal hydrogen bonding as well as
C-bonding4
.
Sieve analysis
Sieve analysis was performed and results are shown in Figure 8,
both IPA and water formed granules shows even distribution of
the particles at 55% of the granulating fluid. Even distribution is
also seen at 50% of granulating fluid but with more number of
fines. This suggests that 50–55% of granulating fluid is adequate
for the granulation.
Angle of repose
Powder is considered to be of excellent flowability if AOR lies in
25
–30
whereas if AOR lies in 31
–35
powder is considered to
be good flowable. Similarly if AOR is 36
–40
it is fairly
Figure 6. Compressibility as a function of increasing granulating fluid.
Figure 5. Aeration as a function of increasing granulating fluid. Figure 7. Tablet hardness as a function of increasing granulating fluid.
DOI: 10.3109/03639045.2014.900080 End point determination 749
Downloadedby[LIULibraries]at12:5516May2016

8. flowable and 41
–45
it is passable and above 46
powders is
considered to be of poor flowability29
. AOR of water and IPA
granules are shown in Table 1. All granules lie in an excellent
flowability range so AOR is not a suitable method to conclude
which one is better as compared to other.
Thermal analysis
Thermal Analysis was performed on wet granules obtained by
using water and IPA as granulating agents. Figure 9 shows the
overlay of thermograms of water and IPA granules, respectively.
The thermograms of the MCC-102 using IPA shows two peaks
due to the presence of water in IPA and presence of moisture in
MCC 102. Delta H values were calculated with increasing amount
of granulating fluid. Delta H represents the total enthalpy change
in the system. This is obtained by integrating the area under the
curve in the DSC. It is shown that MCC-102 absorbs granulating
fluid as the amount increases. Delta H values were calculated and
it has been seen that it increases with increasing amount of
granulating fluid.
Mixing time and end-point determination using thermal effusivity
Mixing time was optimized using effusivity measurements;
Figure 10(a) shows the effusivity measurements as a function of
the mixing time. After 3 min of mixing the effusivity readings
does not show any significant changes suggesting that no
significant changes are observed if mixing time is increased,
hence all the samples were mixed for 3 min at 70 rpm after 30 s of
granulating fluid addition.
Figure 8. Mass retained on sieves.
Figure 9. Overlay of thermograms.
Table 1. Angle of repose as a function of increasing granulating fluid.
Water added IPA (70%) added
% w/w granulating fluid Angle of repose Standard deviation Angle of repose Standard deviation
0 26.37 0.95 26.37 0.95
35 26.95 1.31 23.27 0.99
45 30.29 1.95 28.03 1.04
50 27.26 1.61 27.78 0.77
55 29.48 2.67 28.32 0.96
750 S. P. Chaudhari R. H. Dave Drug Dev Ind Pharm, 2015; 41(5): 744–752
Downloadedby[LIULibraries]at12:5516May2016

9. Thermal effusivity measurements were used to determine the
end-point of wet granulation. Effusivity is directly proportional to
the heat capacity, thermal conductivity and density. Here we used
water and IPA as granulating agents. Water has highest effusivity
($1600 Ws1/2
/m2
K). As the amount of water increases, it will
show rise in effusivity values as seen from Figure 10(b). It is
observed that after the addition of 55% w/w of granulating fluid
there is sudden jump in the effusivity values. This suggests that
initially MCC-102 absorbs the solvent and after certain point
(55%) it starts to show on the surface of MCC-102 resulting in
over-granulation. Figure 10(b) shows the effusivity as the function
of addition of water and IPA on lab and feasibility scale batches
and depicts the regions for under, optimum and over-granulation.
Conclusion
Rheological measurements like BFE, SE, aeration and compres-
sibility results show IPA forms granules with good flowability and
compressibility. Water forms hard and strong granules and its
compressibility reduces as the water increases. Effusivity data
shows that for proper granule formation, 50 to 55% of the
granulating fluid is required and the data is in agreement with the
DSC. Effusivity gives highly reproducible results. Traditionally
used empirical approaches like angle of repose could not
differentiate the flowability of the powders.
Declaration of interest
The authors report no declaration of interest.
References
1. Sheskey PJ, Hendren J. The effects of roll compaction equipment
variables, granulation technique, and HPMC polymer level on a
controlled-release matrix model drug formulation. Pharmaceut
Technol 1999;23:90–9.
2. Bacher C, Olsen PM, Bertelsen P, Sonnergaard JM. Compressibility
and compactibility of granules produced by wet and dry granulation.
Int J Pharm 2008;358:69–74.
3. Buckton G, Yonemochi E, Yoon WL, Moffat AC. Water sorption
and near IR spectroscopy to study the differences between micro-
crystalline cellulose and silicified microcrystalline cellulose before
and after wet granulation. Int J Pharm 1999;181:41–7.
4. Reier GE, Shangraw RF. Microcrystalline cellulose in tableting.
J Pharm Sci 1966;55:510–14.
5. Westermarck S, Juppo AM, Kervinen L, Yliruusi J. Microcrystalline
cellulose and its microstructure in pharmaceutical processing. Eur J
Pharm Biopharm 1999;48:199–206.
6. Nakai Y, Fukuoka S, Nakajima S, Yamamoto K. Crystallinity and
physical characteristics of microcrystalline cellulose. II. Fine
structure of ground microcrystalline cellulose. Chem Pharm Bull
1977;25:2490–6.
7. Millili GP, Wigent RJ, Schwartz JB. Differences in the mechanical
strength of dried microcrystalline cellulose pellets are not due to
significant changes in the degree of hydrogen bonding. Pharm Dev
Technol 1996;1:239–49.
8. Dreu R, Sˇirca J, Pintye-Hodi K, et al. Physicochemical properties of
granulating liquids and their influence on microcrystalline cellulose
pellets obtained by extrusion-spheronisation technology. Int J Pharm
2005;291:99–111.
9. Balaxi M, Nikolakakis I, Kachrimanis K, Malamataris S. Combined
effects of wetting, drying, and microcrystalline cellulose type on the
mechanical strength and disintegration of pellets. J Pharm Sci 2009;
98:676–89.
10. Zoglio MA, Huber HE, Koehne G, et al. Physical aspects of wet
granulations II: factors involved in prolonged and excessive mixing.
J Pharm Sci 1976;65:1205–8.
11. Le´onard G, Bertrand F, Chaouki J, Gosselin PM. An experimental
investigation of effusivity as an indicator of powder blend uniform-
ity. Powder Technol 2008;181:149–59.
12. Ghorab M, Chatlapalli R, Hasan S, Nagi A. Application of thermal
effusivity as a process analytical technology tool for monitoring and
control of the roller compaction process. AAPS PharmSciTech
2007;8:E155–61.
13. Fariss G, Keintz R, Okoye P. Thermal effusivity and power
consumption as PAT tools for monitoring granulation end point.
Pharmaceut Technol 2006;30:60–72.
14. Virtanen S, Antikainen O, Ra¨ikko¨nen H, Yliruusi J. Granule size
distribution of tablets. J Pharm Sci 2010;99:2061–9.
15. Shi L, Feng Y, Sun CC. Roles of granule size in over-
granulation during high shear wet granulation. J Pharm Sci
2010;99:3322–5.
16. Holm P, Schaefer T, Larsen C. End-point detection in a wet
granulation process. Pharm Dev Technol 2001;6:181–92.
17. Miwa A, Yajima T, Itai S. Prediction of suitable amount of water
addition for wet granulation. Int J Pharm 2000;195:81–92.
18. Otsuka M, Mouri Y, Matsuda Y. Chemometric evaluation of
pharmaceutical properties of antipyrine granules by near-infrared
spectroscopy. AAPS PharmSciTech 2003;4:142–8.
19. Frake P, Greenhalgh D, Grierson SM, et al. Process control and end-
point determination of a fluid bed granulation by application of near
infra-red spectroscopy. Int J Pharm 1997;151:75–80.
20. Gamble JF, Dennis AB, Tobyn M. Monitoring and end-point
prediction of a small scale wet granulation process using acoustic
emission. Pharm Dev Technol 2009;14:299–304.
Figure 10. Effusivity as a function of time and increasing granulating fluid.
DOI: 10.3109/03639045.2014.900080 End point determination 751
Downloadedby[LIULibraries]at12:5516May2016

10. 21. Kachrimanis K, Karamyan V, Malamataris S. Artificial neural
networks (ANNs) and modeling of powder flow. Int J Pharm 2003;
250:13–23.
22. Okoye P, Wu SH, Dave RH. To evaluate the effect of various
magnesium stearate polymorphs using powder rheology and thermal
analysis. Drug Dev Ind Pharm 2012;38:1470–8.
23. Faure A, Grimsey IM, Rowe RC, et al. Process control in a high
shear mixer-granulator using wet mass consistency: the effect of
formulation variables. J Pharm Sci 1999;88:191–5.
24. Picker KM, Hoag SW. Characterization of the thermal properties of
microcrystalline cellulose by modulated temperature differential
scanning calorimetry. J Pharm Sci 2002;91:342–9.
25. Trivedi MR, Dave RH. To study physical compatibility between
dibasic calcium phosphate and cohesive actives using powder
rheometer and thermal methods. Drug Develop Indust Pharmacy.
Available from: http://informahealthcare.com/doi/abs/10.3109/
03639045.2013.838576 [last accessed 20 Feb 2014].
26. Dave RH, Wu SH, Contractor LD. To determine the end point of wet
granulation by measuring powder energies and thermal properties.
Drug Dev Ind Pharm 2012;38:439–46.
27. Millili GP, Schwartz JB. The strength of microcrystalline cellulose
pellets: the effect of granulating with water/ethanol mixtures. Drug
Dev Ind Pharm 1990;16:1411–26.
28. Staniforth JN, Baichwal AR, Hart JP, Heng PWS. Effect of
addition of water on the rheological and mechanical
properties of microcrystalline celluloses. Int J Pharm 1988;
41:231–6.
29. Chapter 1174. Powder flow. In: United States Pharmacopeia and
National Formulary (USP 30-NF 25). Rockville (MD): US
Pharmacopeial Convention; 2007.
752 S. P. Chaudhari R. H. Dave Drug Dev Ind Pharm, 2015; 41(5): 744–752
Downloadedby[LIULibraries]at12:5516May2016