Comparative impact of different binder addition methods, binders and diluents
on resulting granule and tablet attributes via high shear wet granulation

Dinesh M. Morkhade

PII: S0032-5910(17)30576-4
DOI: doi:10.1016/j.powtec.2017.07.038
Reference: PTEC 12680

To appear in: Powder Technology

Received date: 21 March 2017

Revised date: 13 June 2017
Accepted date: 12 July 2017

Please cite this article as: Dinesh M. Morkhade, Comparative impact of different binder
addition methods, binders and diluents on resulting granule and tablet attributes via
high shear wet granulation, Powder Technology (2017), doi:10.1016/j.powtec.2017.07.038

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 ACCEPTED MANUSCRIPT

Comparative impact of different binder addition methods,

binders and diluents on resulting granule and tablet attributes
via high shear wet granulation

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Dinesh M Morkhade

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Piramal Healthcare Ltd., Whalton Road, Northumberland, NE613YA, United Kingdom.
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ABSTRACT

This study investigated comparative impact of different binder addition methods (pouring,
dripping, spraying), binders and diluents on resulting granule and tablet attributes via high
shear wet granulation. Lactose monohydrate and mannitol as diluents, and hydroxypropyl

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methylcellulose (HPMC E5) and polyvinylpyrrolidone (PVP K30) as binders were used.
Granules were characterized for morphology, bulk-density, tapped-density, flow, size,

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segregation-potential and friability. To determine granule friability, procedure described in
European Pharmacopoeia was slightly modified to reduce manual-variations and obtain

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appreciable discrimination between the formulations. Binder-diluent affinity was assessed by
measuring contact angles of diluent-dispersion droplets on binder films over a period of time.

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All blends were pressed at the same compression force and resulting tablets were
characterized for pharmacotechnical properties. Results revealed that the binder addition
methods altered granule-shape, which predominantly governed the granule flow. The binder

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addition by spraying increased fines, blend segregation-potential, granule friability, tablet
tensile-strength and tablet disintegration-time; binder addition by pouring showed an opposite
impact. Mannitol granules exhibited lower bulk density, superior flow, lower segregation-
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potential and higher friability than their lactose counterparts. Amongst binders, PVP
produced more friable granules compared to HPMC. The high polydispersity-index of
polymer-binder induced non-homogeneity facilitating the blend segregation-potential. Due to
higher affinity, HPMC was suitable binder for mannitol, and PVP for lactose to promote
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granule growth. The binder-diluent affinity dominated viscosity and surface tension of binder
solution to improve granule size. Increase in granule size decreased granule-friability, which
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subsequently decreased tablet hardness, tensile-strength and disintegration-time. Mannitol

produced harder tablets, and lactose tablets disintegrated faster by all binders and binder
addition methods.
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Keywords: Dripping, Spraying, Mannitol, Lactose, binder polydispersityindex, Granule friability

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1. Introduction

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A well designed and executed formulation development program successfully delivers

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molecule to market. There are two principal domains; a new chemical entity (NCE) and a
generic formulation. In NCE formulations, scientists can use the number of pharmaceutical

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excipients and thus it is important to know how the different excipients behave and affect

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various formulation attributes. On the other hand, in generics the applicable patents and
regulatory requirements usually limit the choice of excipients and their amounts in

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formulation [1], and therefore a good understanding of engineering aspects such as
equipment principles and process parameters is essential for the generic product
development. Nevertheless, in both the domains (NCE and generic), knowledge from drug
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properties, excipient properties, equipment aspects and process parameters is prerequisite for
successful formulation development. In this study, we thus aimed to explore two aspects
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namely the components (different diluents and binders) and the process (different binder
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addition methods) for their impact on various granule and tablet attributes via high shear wet
granulation. Lactose monohydrate and mannitol in diluents, and HPMC and PVP in binders
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are the most commonly used pharmaceutical excipients and therefore the present study used
them to prepare granules by high shear wet granulation.
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Granulation is a well-known technique, which has been widely used in the field of
pharmaceutical science to improve the flow property of blends, densify the blends and
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prevent segregation of low dose actives in tableting to achieve content uniformity. The
aqueous granulations, in addition, provide moisture to blends to improve their compressibility
[2] and thus prevent API degradation in few instances [3]. Amongst several granulation
techniques, the wet and dry granulation are the most commonly used techniques in research
as well as manufacturing domains. Wet granulation can be performed by high shear, low
shear or top-spray process using aqueous or organic solvent as a binder medium. Since water
is safe and cost effective, it remains a preferred solvent for the purpose of wet granulation. In
aqueous granulation, a binder solution (purified water or binder dissolved in water) is usually
poured on the rotating or fluidized blends in the granulator. The resulting granules and their
tablet properties can be influenced by a number of excipients and process attributes, and

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therefore scientists have thoroughly explored the granulation and tableting domains over the
past many years.
A number of studies have been published investigating the impact of drug properties
[4,5], diluent grades and particle size [6,7], wettability of blend [8], excipients surface free

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energy [8,9], molecular weight of binder [10], physical state of binder [11], amounts of

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binder [12], granulation methods [13], types of equipment [14], batch size [15,16], impeller

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design [17], tip speed [18-20] and kneading time [21] on the various granules and tablet

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attributes. In the above studies, however, those specifically dealt with high shear wet
granulation, binder solutions were added mostly by the manual pouring technique. In

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contrast, recently an attempt was made by Oka et al. [22] to incorporate the binder solution
using pre-calibrated peristaltic pump in a drip fashion through a tube in the granulator. They
found that small particles (API or excipients) have tendency to percolate to the bottom of the
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beds during mixing in high shear granulator, and the binder addition by dripping can produce
either subpotent or superpotent granules. Studies have also shown that the state of binder i.e.
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dry (added in dry blends) or wet (added as a solution) greatly influences the resulting granule
and tablet attributes via high shear wet granulation [23-24]. The above details in particular
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propose that along with other crucial factors, the way (form) binder access and deals with the
powder beds in high shear wet granulation markedly affects the granule and tablet
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characteristics.
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Despite the fact that binder addition methods can have an appreciable impact on
granule geometry, density, drug content, particle size, porosity, flow, segregation and
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friability, which subsequently affect the final tablet properties, there is no study in literature
describing the impact of different binder addition methods specifically pouring, dripping and
spraying in presence of commonly used diluents and binders on resulting granule and tablet
attributes via high shear wet granulation. Present study was thus undertaken with an objective
to assess the comparative impact of different binder addition methods, diluents and binders
on various granules and tablet attributes via high shear wet granulation. The study outcomes
will help understanding the interplay of material and process impact on granules and tablet
properties to facilitate development of immediate release tablet formulations containing
different APIs.

2. Materials and methods

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2.1 Materials

Microcrystalline cellulose (MCC) (Avicel PH 101, FMC Biopolymer, Ireland),

lactose monohydrate (Pharmatose 200M, DMV-Fronterra Excipients, Germany), mannitol

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(Pearlitol 50C, Roquette, France), HPMC (Methocel E5 premium LV, Dow Chemical

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Company, Midland), PVP (Kollidon 30, BASF, Germany), croscarmellose sodium (Ac-

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DiSol, FMC Biopolymer, Ireland), colloidal silicon dioxide (Aerosil 200 pharma, Evonik
Industries, Germany), talc (Imerys talc, Italy), magnesium stearate (Peter Greven, Germany)

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were used from the commercial source.

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2.2 Granulation

The batch size was 3000 tablets (1.35 kg) for each formulation. All excipients (as per
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Table 1 and 2) except colloidal silicon dioxide, talc and magnesium stearate were sifted
through ASTM 30 mesh and placed in high shear granulator (5 L bowl equipped with a three-
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blade impeller and four-blade horizontal chopper). Binder to make 4.0% w/v solution in
purified water was spared and remaining was included in initial dry mix. Dry mixing was
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performed at impeller tip speed of 4.6 m/sec for 5 min. Separately, weighed amount of either
HPMC or PVP was dissolved in purified water (to make 4.0% w/v solution) and stirred for 45
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min to ensure polymer hydration. This was used as binder solution to granulate the dry mix in
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high shear granulator. Amount of binder solution utilized was 60% w/w of dry mix weight,
which was selected based on initial screening trials. Binder solution was added either by
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pouring, dripping or spraying method as described below;

In pouring method, binder solution was poured manually from stainless still vessel in
granulator to complete binder addition in 3 min by continuously monitoring a stopwatch.
In dripping method, binder was allowed to drip through stainless still shaft having three
arms (each with multiple openings as shown in Fig. 1A). Solution was conveyed to
dripper/sprinkler and eventually to granulator using conveying tube and peristaltic pump (set
at 20 rpm).
In spraying method, spray gun with 1.0 mm nozzle provided with atomization and fan air
system was fixed at a solution pouring port of granulator (illustration in Fig. 1B). Binder
solution was conveyed to the granulator by peristaltic pump (set at 56 rpm). Spray pressure
and fan air pressure were maintained at 0.3 bars till the completion of binder addition.
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In all the cases, total binder solution was delivered in 3 min. Post binder addition, wet
mass was kneaded at impeller tip speed of 6.4 m/sec and chopper speed of 1440 rpm for 45
sec. Wet mass was dried in fluid bed dryer at a product temperature of 40 ± 2°C till loss on
drying (LOD) achieved was 0.3±0.1% more than the LOD (practically determined) of initial

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dry mix of that respective batch. Dried granules were milled using quadro comil equipped

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with 1016 µ grated screen and square blade (74 mm diameter) rotating at 2500 rpm without

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spacers.

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2.3 Granule characterization

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Milling may subdue discrimination between formulations in few instances. Therefore,
unmilled as well as milled granules were characterized for bulk density, tapped density,
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Carr’s index (CI), Hausner ratio (HR) and granule: fine portions. Milled granules were
additionally characterized for morphology, flow properties, particle size and granule
friability.
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2.3.1. Morphology
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Morphology of native excipients (diluents) and milled granules was examined by

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scanning electron microscopy (Electron optical services, DAH15P102, England). Granule

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samples were coated with gold/palladium mixture to make specimens and examined using
Genie 3000 software.
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2.3.2. Bulk and tapped density

Bulk and tapped density were determined as per method described in USP (USP32–
NF27) [25] using Bulk and tap density tester (JV 2000, Copley, England).
2.3.3. Granule flow property

Flow properties were studied by CI and HR values as per the conventional equations.
In addition, the flow was also evaluated using ring shear tester (Dietmar Schulze ring shear
tester, RST-XS, Germany). Granules were filled gently in sample cell and the excess material
was removed from surface, which was then smoothened using a scraper without applying any
stress to the sample. The cell was placed on a mounting stand and the lid was placed on it.
Loading and tie rods were attached to the lid. During the measurements of normal load, pre-
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shear was adjusted at 5000 Pa. It is the load under which the sample is consolidated and kept
in a steady state. Shearing was then proceeded at lower normal loads of 1000, 2000, 3000 and
4000 Pa consequently. The ratio of the consolidation stress to unconfined yield strength is
termed as flow function index (ffc); higher ffc values indicate better flow. Results were

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analyzed using RST Control 95 software.

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2.3.4. Segregation potential

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For segregation potential, pretest was carried out to find appropriate air flow requisite
to fluidize sample adequately. About 50 g sample was then placed in fluidization segregation

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tester (FFT1026, Jenike and Johanson, M.A, USA), which was operated at air supply of 25
psi and ramp to high, ramp to low, ramp to zero and hold high for 30 sec. Hold low span was
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120 sec. The apparatus divides fluidized sample in three sections, which can be collected
separately in top, middle and bottom cells of the instrument. Content of each cell was
weighed carefully and sieved over ASTM 60 mesh in a sieve shaker (V81, Glen Creston Ltd.,
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England) at 2 mm vibrations for 2 min. The retained portion was considered as granules and
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passed as fines.

2.3.5. Granule size

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For particle size determination, in house method was developed on particle size
analyzer (System-Partikel-Technik, RODOS T4.1, Sympatec, GmbH). About 1 g blend
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sample was placed on the conveyor belt of apparatus and particle size was determined at
primary pressure of 2.1 bar and vacuum depression of 70 ± 5 mbar using R6 0.5/9.0, 1750
µm lens. The particle size of diluents was determined at primary pressure of 3 bars and
vacuum depression of 70 ± 5 mbar using R4 0.5/1.8, 350 µm lens.

2.3.6. Granule friability

A 10 g sample was sieved on ASTM 100 mesh in a sieve shaker (V81, Glen Creston
Ltd., England) at 2 mm vibrations for 2 min. Sieve shaker was used to standardize sieving
step and thus to mitigate variations those otherwise would occur due to manual sieving and
handling. Retained portion was retrieved carefully and charged to glass container (105 mL),
which was then secured in granule friabilator (EGF-1, Electrolab, India). Sample was
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oscillated at 200 strokes per min for 2 min and sieved again through ASTM 100 mesh by
sieve shaker before weighing. The method was slightly modified from European
Pharmacopoeia recommendation to mitigate variations in sieving and parameters used were
based on our experience to discriminate adequately between the various granule-formulations

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with this instrument.

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2.4. Contact angle

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To understand the binder-diluent affinity, 30% w/v solution of binder (methocel E5
premium LV and kollidon 30) was prepared in purified water and allow to hydrate for 45

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min. Rectangular glass slides (typically used for microscopy) were dipped 5 times manually
in the binder solution and dried overnight at 42 ± 2°C in oven. Post drying and cooling to
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room temperature, slides were placed on a horizontal platform and a drop (100 l) of either
lactose monohydrate: Avicel PH 101 (1:1) or mannitol: Avicel PH 101 (1:1) dispersion
(made as 50% w/w in purified water) was carefully placed over smooth surface of binder film
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from a distance of about 5 mm. The contact angle of dispersion droplet was measured
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manually using a protractor and a magnifying glass at 1 min interval up to 5 min.

2.5. Preparation of tablets

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Extragranular materials (except magnesium stearate) were sieved through ASTM 30

mesh and mixed with milled granules in a bin blender rotating at 21 rpm for 10 min.
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Magnesium stearate (ASTM 60 mesh passed) was added and mixed at 21 rpm for 3 min.
Final blends were compressed on a 10 station single rotary compression machine (Korsch XL
100, Germany, Euro B tooling) to form 10.32 mm round standard biconvex tablets with a
target weight of 450 mg. The compression force was kept constant to 16 KN for all
formulations. The compression force was selected based on initial screening trials to achieve
tablet hardness in a conventional range of 10-20 KP.

2.6. Evaluation of tablets

All testing was performed in triplicate. For each, 40 tablets were randomly sampled. 10
tablets were evaluated for thickness (micrometer, Mitutoyo, Japan) and hardness (Erweka,

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TBH 125-D/TD, Germany). Weight variation was performed on 20 tablets using calibrated
Mettler Toledo balance. For friability, 15 tablets were weighed and placed in friabilator (FRV
2000, Copley Scientific Ltd., UK) and friability was determined at 25 rpm for 4 min (100)
and 12 min (300 revolutions). Disintegration test was performed on 6 tablets without the use

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of disc by disintegration tester (DTG 2000, Copley Scientific Ltd., UK) having a purified

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water maintained at 37 ± 1°C.

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The statistical analysis (one way ANOVA and unpaired t-test) was performed using

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GraphPad Prism software (GraphPad Software Inc., CA, version 3.02, April 2000)

3. Results and Discussion

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Lactose monohydrate is termed as lactose in following sections;
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3.1. Granule morphology

It was observed that the binder addition by spraying technique improved sphericity of
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granules, whereas the binder addition by pouring produced irregular granules (Fig. 2). This
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can be explained as; in a wet granulation, the initial mixing of liquid with solid is an
important parameter in nucleation. Nucleation is the first stage of granule formation and it
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describes the formation of nuclei as a result of capturing of powder particles by the binder
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droplets. Litster et al. [26] showed that spraying a binder solution on moving powder bed can
result in nuclei, which size is determined by the size of the sprayed droplets. They further
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clarified that at a low spray pressure, the system operates in the drop controlled regime,
where one drop forms one nucleus. This suggests that the binder addition by spraying (at a
low spray pressure) can produce several discrete nuclei in the top layers of powder bed that
can be converted into granules mostly by the layering mechanism. There are two general
granule growth mechanisms; layering and coalescence. Coalescence is collision of two
particles to form a bigger particle. In order for this to happen particles must collide with a
great energy. In a high shear granulator, greater energy exists in the lower-half of powder bed
due to high impeller work at the bottom of the bowl. On the other hand, layering is when the
fine particles stick to the surface of larger particle/nucleus, and it happens when the impact
forces are low. Since the upper-half of powder bed in the granulator moves relatively slowly,
one can expect layering as a principle granule growth mechanism in the top layers of powder
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bed particularly when the binder is added by the spraying technique. The granules formed by
layering mechanism are more regular and spherical than the granules formed by coalescence
and attrition. Also, Emady et al. [27] studied the single drops impacting static powder beds to
explain different granule shapes. They identified three granule growth mechanisms;

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tunneling, spreading, and crater formation. Tunneling occurred for loose, cohesive powder

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beds, and it always produced round granules, spreading produced flat disks, and the crater

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mechanism produced granules of varying shapes. It is known, for instance, that the powder

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beds needing granulation usually contain the loose cohesive powders, and we noticed that
during mixing and granulation in the high shear granulator, top layers of powder bed revolve

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very slowly. This along with the fact that we obtained round granules when the binder was
added by spraying technique, suggests a possibility that the granule formation (when binder
was added by spraying), in addition to layering, followed the tunneling mechanism (as
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described by Emady et al. [27]) resulting in round granules. On the other hand, since binder
addition by pouring delivers more amount of binder solution to the lower half of powder bed,
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which also has a greater energy due to the high impeller work, coalescence and attrition can
be expected as the primary granule growth mechanism by binder pouring technique to yield
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the irregular granules.

Regarding the impact of binders, PVP produced spherical granules compared to
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HPMC (Fig. 2). Johansen and Schaefer [28] studied the impact of interaction between
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powder particle size and binder viscosity on agglomerate formation via melt granulation.
They found that the low viscosity binder with small particle-size powders, and the high
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viscosity binder with large particle-size powders forms spherical agglomerates. In the present
study, the powders had smaller particle size (all excipients with D50 < 75 µm) and PVP is a
low viscosity binder (than HPMC) [29]. Therefore, it seems that the finding from Johansen
and Schaefer [28], though was based on melt granulation, was also applicable to the high
shear wet granulation wherein the binders were added in the form of solution.
SEM revealed that the exterior of the lactose based granule contained both lactose and
MCC particles, whereas the exterior of mannitol based granules principally contained
mannitol crystals (Fig. 3). This is discussed in detail in section 3.9.3.

3.2. Bulk density

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3.2.1. Impact of binder addition method on granule bulk density

The binder addition by dripping technique produced granules with the highest bulk
density, whereas the binder addition by spraying technique produced granules with the least

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bulk density (Table 3). The trend was similar in unmilled and milled granules and did not

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change with the change in diluent and binder type. So, it can be stated that the granule bulk

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density increased in order when the binder was added by spraying < pouring < dripping
technique. It was observed that the binder addition by pouring produced bigger granules

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(Table 4), while the binder addition by spraying yielded spherical granules (Fig. 2). Both the
increase in particle size and sphericity of granules reduced granule bulk density conceivably

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by increasing the voids in blends. We further noticed that the binder addition by pouring
technique produced several granules with structures that facilitate the voids in blend;
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representative particles are shown in Fig. 4.

3.2.2. Impact of binders on granule bulk density

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In lactose formulations, HPMC produced granules with the higher bulk density
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compared to PVP, whereas in mannitol formulations, the impact of binder was inverse.
Generally the bulk density depends on the volume of the bulk; lower the volume higher is the
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bulk density when the mass is same. It can be seen from Table 3 and 4 that HPMC/lactose
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granules had more fines and smaller particle size than the PVP/lactose, and PVP/mannitol
granules had more fines and smaller particle size than the HPMC/mannitol granules. Fines
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have propensity to percolate and fill the granular voids and thus the blends containing more
fines can be expected to exhibit higher bulk density than the blends having less fines.
Similarly, the blends containing smaller granules retain less voids in their bulk and thus
exhibit higher bulk density than the blends containing bigger granules.

3.2.3. Impact of diluents on granule bulk density

The diluent showed significant impact (p < 0.0001) on the granule bulk density;
lactose formed granules of higher bulk density compared to mannitol by all binders and
binder addition methods (Table 3). This was because of the higher bulk density of native

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lactose (Pharmatose 200M) compared to mannitol (Pearlitol 50C), which also suggests that
lactose retains less voids compared to mannitol in its bulk.

3.3. Tapped density

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Tapped density indicates the ability of material to undergo reduction in volume with
applied taps. Together with bulk density, it contributes to flow prediction by CI and HR. It is

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conceivable that along with other factors, geometry can markedly influence the granule

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tapped density; irregular and smaller granules would have higher tapped density than the
spherical and bigger granules due to less voidage and greater inter-particle locking ability in

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the former.
The granule taped density followed the same trend as of bulk density for the impact of
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all variables of this study. However, it is noteworthy that the impact of binders on granule
bulk and taped density was more prominent in lactose than mannitol formulations suggesting
that lactose was more sensitive than mannitol for binder change affecting the granule bulk
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and taped density. This was also supported by the contact angle observations wherein the
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difference in affinity of different binders was greater in the case of lactose compared to
mannitol (Fig. 5A and B).
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3.4 Carr’s index and Hausner ratio.

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3.4.1. Impact of binder addition method on CI and HR

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In most of the trials, the binder addition by spraying technique improved sphericity of
granules (Fig. 2), and thus lowered the granule CI values (indicating better flow) The general
experience with bulk solid is that the flowability increases with increasing particle size.
However, formulations F11 and F12 despite of their smallest particle size (Table 4) showed
the lowest CI and the highest ffc values (superior flow) (Table 3) indicating that the granule
shape prevailed over other attributes such as granule size and density to improve the granule
flow. Notably, the granulations (milled granules) of this study had particle size (D50) in the
range of 93-255 µm and bulk density in the range of 0.52 to 0.68 g/ml.

3.4.2. Impact of binders on CI and HR

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Amongst the binders, PVP produced granules with the lower CI and HR values
compared to the HPMC. (Table 3). As can be seen from Fig. 2, PVP based granules were
relatively spherical and thus achieved the better flow. This was in agreement with Patel et al.
[30], who observed that the granule flow was improved with PVP as a binder than HPMC;

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though their study employed only lactose granulations.

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3.4.3. Impact of diluents on CI and HR

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In most of the cases, mannitol granules showed lower CI than their lactose
counterparts (based on milled granules). CI value decreases with the decrease in difference

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between bulk and taped density. To understand why mannitol granules had less difference
between the bulk and taped density (thus lower CI), we compared granule particle size by
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Sympatec (Table 4). There was no definite correlation between the granule particle size and
the difference in their bulk and taped density as the mannitol/HPMC granules were bigger,
whereas mannitol/PVP granules were smaller than their lactose counterparts, and yet the
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mannitol granules had the lower CI values (superior flow). Next, we compared the
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morphology and observed that the shape was comparable between the lactose and mannitol
granulations (Fig. 2). However, the granule: fine portions (Table 3) revealed that mannitol
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formulations contained less fines than their lactose counterparts. In the blends having more
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fines, more and more fines can percolate the granular voids with applied taps lowing the tap
volume and thus increasing the granule taped density (though to a limiting value). Therefore,
it appears that the presence of less fines in mannitol formulations has reduced the difference
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between bulk and taped density lowering the granule CI values.

The HR values were in accordance with the CI values (Table 3). Most of the lactose
granulations had HR values > 1.25 indicating “passable” flow and most of the mannitol
formulations had HR values < 1.25 suggesting the “fair” flow of the granules.

3.5. Ring shear testing

Ring shear testing is a more effective way (compared to CI and HR) to predict the
granule flow property. Milled granules were subjected to the ring shear testing and the data is
summarized in Table 3. The granules prepared by binder spraying technique showed higher

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ffc values compared to the other binder addition methods (Table 3). This was because the
binder addition by spraying imparted sphericity to granules improving their flow (Fig. 2).
The mannitol granules exhibited better flow (higher ffc values) than their lactose
counterparts (Table 3), which was in agreement with the CI and HR observations. Notably,

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there was about 2 fold increase in ffc values when PVP was a binder (by dripping and

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spraying technique) compared to HPMC for mannitol granulations. The ffc value of 4-10

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indicates “easy flowing”, whereas ffc greater than 10 indicates “free flowing” characteristic of

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the blend. The ffc values close to or greater than 10 were achieved only in the formulations
wherein PVP was a binder or the binders were added by the spraying technique, which

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suggests that PVP and binder addition by spraying improved the sphericity of granules
improving their flow property.
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3.6. Contact angle (binder-diluent affinity)

While dealing with heterogeneous systems, it is important to know how the different
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phases will behave when brought in contact with each other. It is well known, for instance,
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that some liquids, when placed in contact with other liquids or solids surface, will remain
retracted in the form of drop, while other liquids may exhibit a tendency to spread and cover
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the surface. The phase affinity can be assessed by measuring the contact angle between the
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phases; lower contact angles indicate higher affinity and lower surface free energy in the
phases.
The contact angles of different diluent-dispersion droplets on binder films over a
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period of time are plotted in Fig. 5A and B. Results revealed that HPMC has higher affinity
towards mannitol, and PVP towards lactose. Looking at the functional groups in these
excipients, it appears that the excipients having similar functional groups showed higher
affinity towards each other; PVP and lactose have carbonyl groups, while HPMC and
mannitol have hydroxyl groups in their structure. Furthermore, HPMC in binders, and lactose
in diluents showed greater difference in affinity towards different diluents and binders,
respectively. Since the high binder-diluent affinity facilitates binder ingress, distribution,
particle-consolidation and granule growth, the impact of binder-diluent affinity can also be
learned through the impact of granule particle size and granule: fine portions on other granule
and tablet attributes as described in the following sections.

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3.7. Granule: Fine portions

3.7.1. Impact of binder addition method on granule: fine portions

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The binder addition by spraying increased fines, and the binder addition by pouring

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reduced fines in the final blends (Table 4). The impact, however, was not statistically
significant (p > 0.05). The binder addition by spraying and pouring respectively deliver the

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smaller and bigger droplets/stream to the powder-bed under granulation. This suggests that

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the amount of fines was inversely proportional to the droplet/stream size of liquid binder
falling on the powder bed in the granulator.

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3.7.2. Impact of binders on granule: fine portions
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Amongst the binders, PVP as a binder for lactose, and HPMC for mannitol reduced
the fines in final blends. This was due to the higher affinity of PVP for lactose, and HPMC
for mannitol (Fig. 5A and B). Since fines can alter granule flow, density, segregation and
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compressibility, this was an important finding that can help formulator choosing an
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appropriate binder based on the diluent to be used in high shear wet granulation. Results of
this study recommend PVP for lactose, and HPMC for mannitol particularly to reduce the
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fines in batch via high shear wet granulation.

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3.7.3. Impact of diluents on granule: fine portions

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Amongst all variables, diluent had significant impact (p < 0.0075) on the granule: fine
portions. In most of the cases, lactose formulations contained more fines (%) than their
mannitol counterparts (Table 3). This can be ascribed to the smaller particle size of lactose
(Table 5) and brittleness of lactose over mannitol. The brittleness of lactose over mannitol is
reported in literature; Chang et al. [31] found that lactose-based granules were finer than their
mannitol counterparts because of the brittleness of lactose compared to mannitol. Though the
granules were produced by roller compaction technique in above study, it confirms the
brittleness of lactose over mannitol contributing to the fines in granulation.

3.8. Granule particle size

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3.8.1. Impact of binder addition method on granule size

The binder addition by pouring and spraying increased and decreased the granule
particle size, respectively (Table 4). This suggests that the granule growth was directly

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proportional to the droplet size of binder solution accessing the powder bed in granulation.

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3.8.2. Impact of binders and diluents on granule size

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The impact of diluents, binders or binder addition methods, as an individual variable,

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on granule particle size was not statistically significant (p > 0.05). This was due to the fact
that the binder and diluent in combination, based on their affinity for each other,
predominantly influenced the granule particle size. PVP as a binder for lactose, and HPMC
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for mannitol increased the granule particle size (Table 4), which was due to the higher
affinity of PVP for lactose, and HPMC for mannitol. Besides the higher affinity for mannitol,
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HPMC yields a solution of higher viscosity and lower surface tension (48 mN/m) than PVP
(68 mN/m) [29], which also facilitates binder ingress, particle consolidation and granule
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growth in high shear wet granulation. Therefore, the impact of HPMC to increase granule
particle size was in agreement with the general hypothesis of wet granulation that the granule
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growth is directly proportional to the viscosity and inversely to the surface tension of binder
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solution. However, the fact that PVP over HPMC produced bigger granules in all lactose
formulations (Table 4), which was due to the higher affinity of PVP for lactose, clearly
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indicates that the binder-diluent affinity prevailed over surface tension and viscosity of binder
solution to promote the granule growth.
Notably, the PVP/lactose granules had bigger particle size compared to both
PVP/mannitol and HPMC/lactose granules (Table 4). As stated earlier, lactose retains less
voids compared to mannitol in its bulk, and PVP yields a solution of lower viscosity than
HPMC [29]. Therefore, we can say, for the blends with less voidage (higher bulk density),
low viscosity binders like PVP are more suitable to achieve the higher granule growth.
Scientists have also studied the impact of microcrystalline cellulose crystallinity and
found that decrease in crystallinity increases the abrasion of material by impeller, which
eventually increases the granule particle size [32]. It has also been reported that PVP is
suitable for low polarity substrate and HPMC for high polarity substrate to facilitate the
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granule growth [33]. In the present study, PVP was suitable for lactose, and HPMC for
mannitol to promote the granule growth, and therefore it seems that lactose is less polar than
mannitol. The above details, however, in particular propose that along with the binder-diluent
affinity, other factors like the voidage in blend, crystallinity of ingredients and the polarity of

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ingredients might influence the granule growth kinetics.

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3.9. Granule friability

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3.9.1. Impact of binder addition method on granule friability

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The binder addition by pouring decreased granule friability, whereas the binder
addition by spraying increased granule friability (Table 4). This was because the binder
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addition by the pouring and spraying produced the bigger and smaller granules, respectively.
The bigger granules can be expected to possess more binder-rich domains [34] that impart
strength rendering the bigger granules less friable than the smaller granules/particles.
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3.9.2. Impact of binders on granule friability

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The binders showed significant (p < 0.05) impact on the granule friability; PVP
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produced more friable granules compared to the HPMC (Table 4). It is mentioned earlier in
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this article that granule friability was inversely proportional to the granule particle size,
however, PVP/lactose granules were bigger than HPMC/lactose granules (Table 4) and yet
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showed the higher friability. This clearly indicates that granule particle size did not solely
influence the granule friability. In a wet granulation, wherein the binders are added in the
form of solution, binders have propensity to form a coating/film (partly if not fully) on the
powder particles and the resulting granules during granulation and drying. Whilst HPMC can
form a tough film, PVP forms a weak and brittle film [35]. The tough HPMC films/coats in
the granule-domains make granules more resistant to fragmentation. In addition, since PVP
yields solution of lower viscosity and has a weak-film forming propensity, it can be expected
that the binder-diluent particles would be held loosely together in the PVP based granules
compared to HPMC. Such granules can undergo more fragmentation when subjected to the
friability test showing the higher friability.

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3.9.3. Impact of diluents on granule friability

The mannitol granules were much more friable than their lactose counterparts (Table
4). This was contrary to the known fact that lactose is brittle than mannitol [31]. This further

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indicates that the excipients and their granule-form (prepared via high shear wet granulation)

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can behave distinctly in terms of friability, which may be due to the dynamics of high shear

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wet granulation. During mixing in high shear granulator, ingredients of different particle size
have tendency to segregate. Therefore, the nuclei and the exterior of the granule may contain

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different proportion of excipients. Morin and Briens [13] prepared granules with 1:1 ratio of
lactose monohydrate and MCC (Avicel PH 101), and noticed that large lactose particles were

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forced towards the side and bottom of the bowl during mixing in high shear granulator and
thus the nuclei contained only MCC, and lactose existed mostly in the exterior of the
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granules. However, the above study did not specify the grade and detail particle size of
lactose that was used. In the present study, SEM revealed that lactose based granules
contained comparable portions of lactose and MCC in the exterior of the granule, whereas the
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exterior of mannitol based granule principally contained mannitol particles/crystals (Fig. 3).
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The blends in present study used either lactose (Pharmatose 200M): MCC (Avicel PH 101) or
mannitol (Pearlitol 50C): MCC (Avicel PH 101) in 1:1 ratio. The particle size of lactose,
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MCC and mannitol was determined by Sympatec and the data is summarized in Table 5.
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Results show that the lactose and MCC had comparable particle size, whereas the particle
size of mannitol was relatively bigger. So, as described by Morin and Briens [13], it appears
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that mannitol, because of its larger particle size, segregated in MCC: mannitol blends,
whereas MCC: lactose blends did not segregate (due to the comparable particle size of these
excipients) during mixing and granulation, and thus the granules from these two distinct
blends showed different excipient-arrangements in the exterior of the granules. Since lactose
based granule contained comparable portions of MCC and lactose, and MCC is less brittle
than mannitol, it showed less friability compared to the mannitol based granules wherein
MCC formed nuclei, and mannitol the exterior of granules. In addition, it appears from Fig. 2
and 3 that mannitol granules had more intragranular pores and crystalline regions compared
to their lactose counterparts. Intragranular pores reduce granule strength, while crystalline
domains encourage granule fragmentation/breakage under stress (oscillations in friability
test) leading to the higher granule friability.
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According to Handbook of Pharmaceutical Excipients [36], solubility of lactose is

slightly higher than mannitol in water. It has also been reported that the increase in excipient
solubility in granulation solvent decreases the solvent requirement and leads to the formation
of less friable granules [37,38]. However, the solubility difference between lactose and

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mannitol in water is very less and thus we anticipate a little contribution from it to the granule

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friability.

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3.10. Segregation potential

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Most of the recent APIs have low solubility and thus are synthesized in the smaller

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particle size. APIs of smaller particle size, post dry mixing in high shear granulator, percolate
to the bottom of the bed rendering top layers of the bed subpotent. Binder solution initially
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access the top layers of powder bed producing subpotent granules and superpotent fines [22].
In contrast, Vromans et al. [39] reported that micronized steroid when granulated with
unmicronized lactose produce superpotent granules and subpotent fines. From these findings,
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however, it is apparent that the coarse and fine fraction of granules may contains substantially
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different amounts of API. Therefore, the factors affecting granule: fine segregation potential
should be evaluated and controlled beforehand to mitigate the content uniformity risk in
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tableting.
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If the bulk of solid containing a mixture of coarse and fine fraction is fluidized, a
layer of fines remain at the top and coarse particles sink downward. In pharmaceutical
manufacturing, this can happen when the particles-stream fed into the dies during tabletting
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drags a significant stream of air with it. The blend segregation tendency in such situation can
be assessed by the fluidization segregation testers. These instruments fluidize the blend, hold
it in a fluidized state for a given period of time and divide it in three parts allowing the
collection of samples in top, middle and bottom cell of the apparatus. Fines have propensity
to accumulate in the top cell and thus more fines (compared to granules) in top cell indicate
the higher segregation potential of the blend.

3.10.1. Impact of binder addition methods on blend segregation potential

In lactose formulations, binder addition technique did not substantially affect the
blend segregation potential (Table 6). On the other hand, in mannitol formulations, binder
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addition by spraying technique facilitated the blend segregation potential. This can be
attributed to the presence of higher amount of fines in the formulations prepared by the
binder spraying technique (Table 3). The mannitol/PVP granulations wherein the binder was
added by spraying technique showed the highest segregation potential, which might be due to

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the presence of the highest amount of fines in this batch amongst all mannitol formulations.

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3.10.2. Impact of binders on granule segregation potential

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Both in lactose and mannitol formulations, PVP based blends showed greater
difference in granule: fine portions between the top and bottom cell of the apparatus (Table

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6), which indicates the non-homogeneity in these blends. Both HPMC and PVP are the
polymeric materials. HPMC is partly O-methylated and O-(2-hydroxypropylated) cellulose
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polymer and PVP is a synthetic polymer consisting of linear 1-vinyl-2-pyrrolidinone groups.
Each polymer has a specific polydispersity index (PI). PI is a ratio of weight average
molecular weight to the number average molecular weight of polymer, which indicates the
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distribution of individual molecular masses in the batch of polymer. PI values close to unity
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show that molecules have the same or comparable molecular weights (MWs), while higher PI
values indicate the presence of fractions with different MWs distributed around the average
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MW. The PI of PVP (K30) is 5.5, while for HPMC (methocel E5 LV) it is about 1. This
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indicates a wide and narrow range of molecular weight distribution in PVP and HPMC,
respectively. The wide range of Mw distribution in PVP can be expected to induce non-
homogeneity in granulation causing the variations in granule: fine portions, which
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subsequently can facilitate the blend segregation potential.

3.10.3. Impact of diluents on granule segregation potential

In lactose formulations, the amount of fines in top cell was 84-90%, while it was only
47-78% in mannitol formulations (Table 6). This clearly indicates that the mannitol blends
had much lower segregation potential than their lactose counterparts. There could be two
reasons; first the presence of higher amount of fines in lactose compared to mannitol
formulations (Table 3), and secondly the presence of more crystalline domains in mannitol
compared to lactose granules (Fig. 3); a network of such crystalline granules in blend could

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impede the escape of fluidized fines to the top cell reducing the percentage of fines in top cell
of the apparatus.

3.11. Physicochemical properties of tablets

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All the blends were compressed at the same compression force of 16 KN and resulting
tablets were characterized for pharmacotechnical properties.

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3.11.1. Tablet hardness and tensile strength

The diluents, binders and binder addition methods influenced tablet hardness via

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granule friability. The increase in granule friability increased the final tablet hardness. In this
study, mannitol over lactose, PVP over HPMC, and spraying over other binder addition
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methods produced tablets with the higher hardness (Table 7). Among the variables of this
study, only diluents showed significant (p < 0.0005) impact on the tablet hardness and tensile
strength. With respect to the binders, Joneja et al. [40] reported that the cellulose based
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binders can produce tablets with the highest toughness, whereas the tablets containing other
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binders like PVP fail by capping and random cracking in the middle. However, we observed
that the tablets containing PVP had higher hardness and tensile strengths compared to their
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HPMC counterparts, which was due to the higher friability of PVP based granules (Table 4).
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Furthermore, since HPMC forms a tough film and PVP a weak and brittle film, HPMC based
granules can be more resistant to fragmentation and inter-particle bonding in tableting to
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reduce the final tablet toughness. Regarding the diluents, mannitol based tablets had higher
hardness and tensile strengths compared to their lactose counterparts, which was in
agreement with Rasenack and Muller [41], who reported that the tabletting factor (T-factor)
of mannitol is superior to lactose. Also, Juppo et al. [42] have studied the effect of amount of
granulation liquid, compression speed and compression force on compressibility and
compactibility of lactose, glucose and mannitol granules and found that mannitol forms the
hardest tablets and lactose and glucose the weakest.
The tablet tensile strength was calculated as per the literature [43]. The impact of
diluents, binders and binder addition methods on tablet tensile strength was based on the
granule friability, and the trend was same as discussed above for the tablet hardness. Based
on our observations from various other tablet formulations and their shipment studies, we can
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say that the tablet tensile strength of > 1.9 indicates satisfactory strength for handling and
transportation. In this study, all the values were > 1.9 suggesting an excellent tablet tensile
strengths from all the formulations.

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3.11.2. Tablet thickness

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According to Food and Drug Administration (FDA, USA), dimensions of solid oral

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generics are critical and should be targeted comparable to the reference product for better

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patient compliance [44]. Understanding the impact of excipients and process parameters on
tablet thickness is therefore important to design an appropriate generic formulation. In this

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study, tablets containing lactose exhibited lower thickness than their mannitol counterparts
(Table 7), which was due to the higher bulk density of lactose compared to mannitol.
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Amongst the binders, tablet thickness was lower when HPMC was a binder for lactose, and
PVP for mannitol granulations. This was attributed to the higher bulk density, more fines and
smaller particle size of these granulations. In the lactose based tablets, thickness was lowest
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when the binders were added by the pouring technique, whereas in mannitol tablets, thickness
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was lowest when the binders were added by the dripping technique. This again was attributed
to the granule bulk density; binders pouring and dripping increased the granule bulk density
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in lactose and mannitol granulations, respectively. Amongst the binder addition methods, the
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binder addition by spraying decreased granule bulk density (Table 3), and thus increased the
final tablet thickness. Overall, the impact of diluents on tablet thickness was significant (p <
0.0001), whereas the binders and binder addition methods did not significantly (p > 0.05)
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alter the final tablet thickness; the change in binder and binder addition method yielded
tablets within mean ± 0.3 mm range, which is a well-accepted range in routine tablet
manufacturing in the pharmaceutical industries.

3.11.3. Tablet friability

In lactose formulations, the binders and binder addition methods did not substantially
affect the tablet friability. Whereas in mannitol formulations, PVP as a binder produced less
friable tablets compared to the HPMC (Table 7). This was due to the higher friability of PVP
based granules compared to HPMC; the tablet friability was inversely proportional to the
granule friability. In lactose formulations, granule friability of > 15% produced tablets with

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appreciable tensile strength and lower friability, whereas in mannitol formulations, the
granule friability of even > 10% produced tablets with high tensile strength and negligible
friability. The lactose based tablets were much more friable compared to their mannitol
counterparts; the data was confirmed at two different revolutions (100 and 300) in friabilator.

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Again, the impact of diluents on tablet friability was significant (p < 0.0001), whereas the

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binders and binder addition methods did not significantly (p > 0.05) affect the tablet friability.

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3.11.4. Tablet disintegration

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There are number of factors that can influence tablet disintegration, some of these are the

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drug properties, excipient properties, type of disintegrant and the tablet hardness. In this
study, lactose and mannitol as diluents, and HPMC and PVP as binders were comparatively
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evaluated. Since lactose and mannitol have comparable solubility, and the disintegrant and
other auxiliary excipients were constant in all formulations, the tablet disintegration time in
present study was principally governed by the tablet hardness and tensile strength, which
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were directly proportional to the granule friability. The impact of diluents, binders and binder
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addition methods on granule friability is described in detail earlier in this report. Overall,
tablet disintegration time increased with the increase in tablet hardness and tensile strength.
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The diluents followed by binders showed substantial impact, whereas the binder addition
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methods could not substantially influence the tablet disintegration time. In this study,
mannitol over lactose, PVP over HPMC and spraying over other binder addition methods
increased tablet disintegration time (Table 7).
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4. Conclusion

This study investigated a comparative impact of different binder addition methods, diluents
and binders on various granules and tablet attributes via high shear wet granulation. Binder
addition methods altered granule shape, which predominantly governed the granule flow.
Binder addition by spraying increased fines, blend segregation potential, granule friability,
tablet tensile strength and tablet disintegration time; binder addition by pouring showed an
opposite impact. Diluents dominated binders and binder addition methods to influence
granule density, segregation potential and friability. Mannitol based granules exhibited lower
bulk and taped density, higher friability, superior flow and lower segregation potential
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compared to their lactose counterparts. The high polydispersity index of polymer-binder

induced non-homogeneity facilitating the blend segregation-potential. The PVP based
granules were more friable compared to the HPMC based granules. Contact angle study
revealed higher affinity of PVP for lactose, and HPMC for mannitol. The binder-diluent

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affinity prevailed over surface tension and viscosity of binder solution to promote granule

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growth. Increase in granule size decreased granule friability, tablet hardness, tensile strength

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and disintegration time. Mannitol produced harder tablets, and lactose tablets disintegrated

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faster by all binders and binder addition methods.

Funding

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This research did not receive any specific grant from funding agencies in the public,
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commercial, or not-for-profit sectors.

Acknowledgments
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The author wish to thank Colin Carr for providing language help for this article.
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[34] J.D. Osborne, R.P.J. Sochon, J.J. Cartwright, D.G. Doughty, M.J. Hounslow, A.D.
Salman, Binder addition methods and binder distribution in high shear and fluidised

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bed granulation, Chem. Eng. Res. Des. 89 (2011) 553-559.

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[35] J.N.C. Healey, M.H. Rubinstein, V. Walters, The mechanical properties of some

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binders used in tableting, J. Pharm. Pharmacol. 26 (1974) 41-46.

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[36] R.C. Rowe, P.J. Sheskey, M.E. Quinn, Handbook of pharmaceutical excipients, sixth
ed. Pharmaceutical Press. (2009)

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[37] J.I. Wells, C.V. Walker, The influence of granulating fluids upon granule and tablet
properties: the role of secondary binding, Int. J. Pharm. 15 (1983) 97-111.
[38] V.H. Dias, J.F. Pinto, Identification of the most relevant factors that affect and reflect
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the quality of granules by application of canonical analysis, J. Pharm. Sci. 91 (2002)
273-281.
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[39] H. Vromans, H.G. Poels-Janssen, H. Egermann, Effects of high-shear granulation on

granulate homogeneity, Pharm. Dev. Technol. 4 (1999) 297-303.
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[40] S.K. Joneja, W.W. Harcum, G.W. Skinner, P.E. Barnum, J.H. Guo, Investigating the
fundamental effects of binders on pharmaceutical tablet performance, Drug Dev. Ind.
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Pharm. 25 (1999) 1129-1135.

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[41] N. Rasenack, B.W. Muller, Crystal habit and tableting behavior, Int. J. Pharm. 244
(2002) 45-57.
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[42] A.M. Juppo, L. Kervinen, J. Yliruusi, E. Kristoffersson, Compression of lactose,

glucose and mannitol granules, J. Pharm. Pharmacol. 47 (1995) 543-549.
[43] A. Aodah, R.S. Bafail, M. Rawas-Qalaji, Formulation and evaluation of fast-
disintegrating sublingual tablets of atropine sulfate: the effect of tablet dimensions and
drug load on tablet characteristics, AAPS PharmSciTech. (2016) 1-10.
[44] FDA (Food and Drug Administration), 2015. Size, shape, and other physical attributes
of generic tablets and capsules.

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Table 1

A base composition for granules and tablets

Ingredients mg/ tablet

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Microcrystalline cellulose (Avicel PH 101) 198.0

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Lactose monohydrate (Pharmatose 200M)
198.0

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OR mannitol (Pearlitol 50C)

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Hydroxypropyl methylcellulose (Methocel
Prem. E5 LV) OR Polyvinyl pyrrolidone 22.0

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(Kollidon 30)
Croscarmellose sodium (Ac-Di-Sol) 19.0
Colloidal silicon dioxide 4.5
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Talc 4.0
Magnesium stearate 4.5
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Total 450.0
P TE
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Table 2

Formulation batch numbers

Batch number F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12

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Lactose      

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- - - - - -
Mannitol - - - - - -      

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HPMC E5    - - -    - - -

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PVP K30 - - -    - - -   
Binder addition technique

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Pouring  - -  - -  - -  - -
Dripping -  - -  - -  - -  -
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Spraying - -  - -  - -  - - 
“” indicates used, and “-” indicates not used. A 40% w/w Avicel PH 101 and 1% w/w each
of talc, aerosil 200 pharma and magnesium stearate were constant in all the blends
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Table 3

Physicochemical properties of granules

Binder Bulk Tapped Granule:

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Carr’s Hausner ffc
Batch addition Granules density density Fine portions

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index ratio value
method (g/mL) (g/mL) (% w/w)

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F1 Pouring Unmilled 0.644 0.843 23.61 1.31 - 60:40

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Milled 0.660 0.858 23.08 1.30 7.2 54:46
F2 Dripping Unmilled 0.66 0.856 22.90 1.30 - 62:38
Milled 0.679 0.863 21.32 1.27 7.9 44:56

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F3 Spraying Unmilled 0.608 0.778 21.85 1.28 - 67:33
Milled 0.642 0.796 19.35 1.24 9.1 41:59
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F4 Pouring Unmilled 0.631 0.806 21.71 1.28 - 64:36
Milled 0.649 0.817 20.56 1.26 7.6 57:43
F5 Dripping Unmilled 0.652 0.808 19.31 1.24 - 67:33
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Milled 0.668 0.823 18.83 1.23 9.2 50:50

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F6 Spraying Unmilled 0.606 0.749 19.09 1.24 - 72:28

Milled 0.624 0.765 18.43 1.23 11.8 44:56
F7 Pouring Unmilled 0.540 0.641 15.76 1.19 - 76:24
P

Milled 0.546 0.679 19.59 1.24 8.0 72:28

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F8 Dripping Unmilled 0.562 0.702 19.94 1.25 - 71:29

Milled 0.566 0.699 19.03 1.23 8.4 64:36
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F9 Spraying Unmilled 0.519 0.617 15.88 1.19 - 70:30

Milled 0.524 0.642 18.38 1.23 9.9 63:37
F10 Pouring Unmilled 0.541 0.637 15.07 1.18 - 74:26
Milled 0.549 0.683 19.62 1.24 8.8 69:31
F11 Dripping Unmilled 0.559 0.694 19.45 1.24 - 72:28
Milled 0.578 0.709 18.48 1.23 13.5 58:42
F12 Spraying Unmilled 0.531 0.634 16.25 1.19 - 84:16
Milled 0.529 0.644 17.86 1.22 17.3 49:51

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Table 4

The particle size and friability of the final milled granules

Batch Binder Granules size (µm) Granule

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addition friability (%

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D10 D50 D90
w/w)

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F1 Pouring 57.85 ± 0.83 131.66 ± 2.34 369.53 ± 1.74 1.49

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F2 Dripping 41.70 ± 0.08 116.45 ± 0.62 314.03 ± 3.22 7.25
F3 Spraying 33.96 ± 0.09 98.17 ± 0.21 267.61 ± 0.31 8.75

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F4 Pouring 73.63 ± 0.08 231.05 ± 0.33 516.80 ±2.07 4.81
F5 Dripping 59.77 ± 0.13 207.13 ± 3.09 484.37 ±0.56 15.02
F6 Spraying 46.13 ± 0.24 129.25 ± 0.11 417.98 ±3.33 17.46
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F7 Pouring 82.01 ± 0.05 255.02 ± 2.42 552.40 ± 9.31 8.05
F8 Dripping 52.16 ± 0.21 221.13 ± 0.36 527.55 ± 2.86 10.85
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F9 Spraying 31.03 ± 0.06 168.22 ± 0.89 453.59 ± 0.13 13.19

F10 Pouring 43.21 ± 1.24 122.28 ± 0.11 347.27 ± 0.24 14.79
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F11 Dripping 36.82 ± 0.91 109.13 ± 0.07 301.93 ± 1.55 23.47

F12 Spraying 33.01 ± 0.04 93.42 ± 0.05 214.56 ± 0.09 25.45
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Table 5

Particle size of excipients as determined by Sympatec

Excipient Particle size (µm)

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D10 D50 D90

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Microcrystalline cellulose 3.8 ± 0.03 48.27 ± 0.08 105.61 ± 0.16

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(Avicel PH 101)

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Lactose monohydrate 3.2 ± 0.08 41.26 ± 0.31 101.43 ± 0.22
(Pharmatose 200M)

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Mannitol (Pearlitol 50C) 16.8 ± 0.05
MA 75.31 ± 0.07 147.38 ± 0.30
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Table 6

Granules and fines in top, middle and bottom cell of fluidization segregation tester

Batch Location of cell in Granules Fines

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segregation tester (% w/w) (% w/w)

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F1 Top 11 89

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Middle 51 49

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Bottom 76 24
F2 Top 14 86

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Middle 39 61
Bottom 81 19
F3 Top 14 86
MA
Middle 54 46
Bottom 83 17
D

F4 Top 10 90
Middle 46 54
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Bottom 93 07
F5 Top 16 84
P

Middle 59 41
CE

Bottom 98 02
F6 Top 13 87
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Middle 72 28
Bottom 94 05
F7 Top 53 47
Middle 59 41
Bottom 72 28
F8 Top 45 55
Middle 65 35
Bottom 69 31
F9 Top 42 58
Middle 69 31

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Bottom 75 25
F10 Top 49 61
Middle 68 32
Bottom 76 24

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F11 Top 43 67

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Middle 62 38

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Bottom 76 24

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F12 Top 22 78
Middle 50 50

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Bottom 79
MA 21
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Table 7

Tablet properties

Tensile

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Binder Hardness Thickness Disintegration Friability* Friability**
Batch strength

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addition (kp) (mm) time (min) (%) (%)
(MPa)

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F1 Pouring 12.5 4.41 2.20 6 0.10 0.34

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F2 Dripping 13.0 4.37 2.33 6 0.12 0.41
F3 Spraying 15.3 4.53 2.58 8 0.09 0.29

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F4 Pouring 16.8 4.45 2.92 9 0.07 0.27
F5 Dripping 17.3 4.51 2.94 11 0.04 0.24
F6 Spraying 18.3 4.58 3.03 11 0.05 0.25
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F7 Pouring 25.6 4.81 3.97 16 Nil 0.07
F8 Dripping 23.3 4.78 3.60 14 0.03 0.09
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F9 Spraying 28.4 4.96 4.15 16 Nil 0.05

F10 Pouring 28.3 4.76 4.41 16 Nil 0.03
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F11 Dripping 32.8 4.73 5.16 21 Nil Nil

F12 Spraying 34.9 4.86 5.26 22 Nil Nil
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*
Friability post 100 revolutions, ** friability post 300 revolutions.
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Hardness values were within ± 1.5 kp, and thickness values were within ± 0.2 mm range for
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all formulations, so only the mean of 3 determination is presented in the table above.

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Fig. 1

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Fig. 2

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Fig. 3
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Fig. 4
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Fig. 5
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Figure Captions
Fig. 1. Granulation set up showing (A) dripping and (B) spraying mechanisms.

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Fig. 2. SEM of granules prepared using various diluents, binders and binder addition

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methods.

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Fig. 3. SEM showing (A) microcrystalline cellulose (Avicel PH 101), (B) lactose

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monohydrate (Pharmatose 200M), (C) mannitol (Pearlitol 50C), (D) lactose-based
granule and (E) mannitol-based granule.

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Fig. 4. SEM showing various granule structures that can facilitate voids in blends

Fig. 5. Contact angles of lactose: microcrystalline cellulose and mannitol: microcrystalline

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cellulose dispersion droplets on (A) PVP films and (B) HPMC films.
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Graphical abstract MA
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Highlights
 Binder addition methods alter granule shape that predominantly governs granule flow.
 Binder-diluent affinity dominates other factors to influence the granule growth.
 PVP as a binder produce more round and friable granules compared to the HPMC.
 High polydispersity index of polymer-binder facilitates blend segregation potential.

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 Mannitol tablets achieve higher hardness, while lactose tablets dintegrate faster.

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