International Journal of Pharmaceutics 608 (2021) 121110

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International Journal of Pharmaceutics

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

Systematic study of paracetamol powder mixtures and granules

tabletability: Key role of rheological properties and dynamic image analysis
Oliver Macho a, Ľudmila Gabrišová a, Jana Brokešová b, Petra Svačinová b, Jitka Mužíková b,
Paulína Galbavá c, d, Jaroslav Blaško c, Zdenka Šklubalová b, *
a
Institute of Process Engineering, Faculty of Mechanical Engineering STU in Bratislava, Námestie slobody 17, 812 31 Bratislava 1, Slovak Republic
b
Charles University, Faculty of Pharmacy in Hradec Králové, Department of Pharmaceutical Technology, Ak. Heyrovského 1203, 500 05 Hradec Králové, Czech
Republic
c
Department of Analytical Chemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Ilkovičova 6, 842 15, Bratislava 4, Slovak Republic
d
Hermes lab systems, Puchovska 12, 83106 Bratislava 3, Slovak Republic

A R T I C L E I N F O A B S T R A C T

Keywords: The aim of this systematic study was to analyze the granulometric and rheological behavior of tableting mixtures
Dynamic image analysis in relation to tabletability by single tablet and lab-scale batch compression with an eccentric tablet machine.
Powder rheology Three mixtures containing 33, 50, and 66% of the cohesive drug paracetamol were prepared. The high
Heckel analysis
compressibility of the powder mixtures caused problems with overcompaction or lamination in the single tablet
High shear granulation
Tabletability
compression method; due to jamming of the material during the filling of the die, the lab-scale batch compression
Paracetamol was impossible. Using high shear granulation, the flow properties and tabletability were adjusted. A linear
relationship between the span of granules and the specific energy measured by FT4 powder rheometer was
detected. In parallel, a linear relationship between conditioned bulk density and the tensile strength of the tablets
at lab-scale batch tableting was noted. The combination of dynamic image analysis and powder rheometry was
useful for predicting the tabletability of pharmaceutical mixtures during the single tablet (design) compression
and the lab-scale batch compression.

1. Introduction
Tablets currently represent the largest portion of all pharmaceutical
preparations. Due to the variable physicochemical properties, the
development of solid dosage forms is generally an empirical and time-
consuming process (Capece et al., 2015) as the resulting properties are
qualitatively and quantitatively influenced by all components (Patel and
Bansal, 2011). To produce pharmaceutical products of the highest
quality, it is necessary to properly understand their composition and
manufacturing process at the stage of dosage form development (Kalaria
et al., 2020).
Flowability and compressibility represent the key properties,
particularly in the direct compaction process (Worku et al., 2017). The
flow and compaction properties of pharmaceutical materials are influ­
enced by many factors: such as particle size and size distribution,
particle shape, surface area and structure, density, and interparticle
interactions, but also environmental factors such as humidity or elec­
trostatic charge as well as the equipment used also have to be considered
(Hirschberg et al., 2019).
Powder flow is not an inherent material property which means that
no single descriptor enables a complete decription of flow behavior (Van
Snick et al., 2018). There are several static and dynamic methods for
determining the flow properties of powder materials and granules, such
as determination of the angle of repose, flow through the orifice,
Hausner ratio, Carr index, avalanche behavior, and shear cell mea­
surements (Blanco et al., 2020), (Ghadiri et al., 2020), (Tan et al., 2015).
Shear testers provide the most detailed description of the behavior of
powder material on a particle–particle basis. Based on the relationship
of normal and shear stress, many detailed characteristics can be esti­
mated from the yield curve by Mohr circle analysis (Carson and Wilms,

Abbreviations: AIF, Angle of internal friction; AIFE, Effective angle of internal friction; PEG, Polethylethylene glycol; API, Active pharmaceutical ingredient; PVP,
Polyvinylpyrrolidone; BFE, Basic Flowability Energy; SE, Specific Energy; CBD, Conditioned bulk density; SI, Stability index; DIA, Dynamic image analysis; WFA,
Wall friction angle; FRI, Flow Rate Index.
* Corresponding author.
E-mail address: sklubalova@faf.cuni.cz (Z. Šklubalová).

https://doi.org/10.1016/j.ijpharm.2021.121110
Received 23 June 2021; Received in revised form 7 September 2021; Accepted 14 September 2021
Available online 20 September 2021
0378-5173/© 2021 Elsevier B.V. All rights reserved.
O. Macho et al.
2006). In addition to traditional shear testers, powder rheometers are
now increasingly used, the main advantage of which is to perform
various static and dynamic tests of the materials under investigation.
Several studies have focused on comparing different types of rheometers
(Koynov et al., 2015), (Berry et al., 2015), (Slettengren et al., 2016) and
(Salehi et al., 2017). Rheometer FT4 (Freeman Technology) has become
often used in pharmaceutical preformulation studies (Wang et al.,
2016a), (Wang et al., 2016b), (Chen et al., 2018a), (Majerová et al.,
2016), (Nan et al., 2017), (Tran et al., 2019).
Inadequate properties of tableting mixtures can result in problems in
the manufacturing process such as feeding of material into a die during
the compaction process, but further this also affects the properties of the
final product such as tensile strength, disintegration time or dissolution
performance (Megarry et al., 2019). Particularly whenever the active
pharmaceutical ingredient is cohesive, the adjustment of its flowability
requires considerable effort in the development of solid dosage forms.
The analgetic and antipyretic drug paracetamol represents a widely used
drug known for poor flowability, bad tabletability, and reduced plastic
deformation during compaction (Taipale-Kovalainen et al., 2018), (Rose
and Kaialy, 2019). In order to improve material flowability and tablet­
ability, various types of excipients are added, such as fillers, binders,
disintegrants, glidants or lubricants (Chen et al., 2018b).
If flow properties of tableting mixtures remain poor even after the
addition of excipients, dry or wet granulation processing is necessary. In
the manufacturing of pharmaceuticals, high shear granulation (HSG) is
the most common method. The reduction of fine particle content
improving the flow properties, increase in density and homogeneity of
tablet components, and better tabletability are the primary aims. Even
though HSG of powder mixtures containing paracetamol has already
been investigated by several authors (Arp et al., 2011), (Albertini et al.,
2004), (Fayed et al., 2017), (Han et al., 2019), understanding material
variability and variance in this unit operation is key to ensuring
adequate consistency of the final product (Stauffer et al., 2019) and
granulometric parameters of the tableting mixtures should be correctly
characterized to avoid mechanical arching in the feeding hopper orifice.
The dynamic image analysis (DIA) method is attractive for its relative
low cost, measurement speed, and ability to provide a wide range of
morphological parameters (Czajkowska et al., 2015), (De Simone et al.,
2018), (Whiting et al., 2019). However, to date, no study has been
published analyzing the parameters obtained from the DIA in relation to
the data obtained from the powder rheometer.
During compaction, the material generally passes through three
phases: an initial stage of particle rearrangement at low compaction
pressure, plastic deformation and fragmentation at medium pressure,
and finally elastic deformation at high pressures (Heckel, 1961). In
addition, the tabletability of the proposed tableting mixtures should be
necessarily identified during the development of new dosage forms and
particularly before the continuous tablet compaction process to avoid
economic loss. The use of batch tablet compaction currently represents a
useful method. In the simplest experimental arrangement of compress­
ibility measurement, the confined sample is exposed to uniaxial load and
the relation between the applied force and the piston position is recor­
ded (Penkavova et al., 2019). Generally, the preliminary processes and
data are enlarged empirically, experimentally validated and further
optimized in a scaled-up process to achieve successful continuous pro­
duction and essential quality parameters of the final products (Bou­
kouvala et al., 2012).
In this regard, the aim of this systematic study was to investigate the
dependence between the granulometric and rheological parameters of
paracetamol-containing powder mixtures and granules. Three types of
mixtures with percentage content of paracetamol 33% to 66% were
prepared and evaluated by dynamic image analysis. The powder mix­
tures and granules prepared by high shear granulation using two types of
granulation liquids with different concentrations were compacted in the
single tablet design machine and the lab-scale eccentric tablet machine
(batch compression) and analyzed by Heckel analysis in order to predict
2
International Journal of Pharmaceutics 608 (2021) 121110
the potential technological problems in the production process.
2. Materials and methods
2.1. Materials
Paracetamol (Acetamidophenol, API, Glentham Life Science, UK)
was used as an Active Pharmaceutical Ingredient (API). Microcrystalline
cellulose (Avicel® PH 101, FMC Biopolymer, Ireland) was used as a dry
binder / filler, maltitol (Maltilite® P200 Pharma, Tereos, France) with
fine particles and sorbitol (Merisorb® 200, Tereos, France) with coarse
particles were used as the sweetening fillers, and magnesium stearate
(Glentham Life Science, UK) as a lubricant. An aqueous solution of
polyvinylpyrrolidone (Povidone K30, PVP, AppliChem, Germany) or
polethylethylene glycol (PEG 8000, AppliChem, Germany) were used as
granulation liquids. Acetonitrile (Merck, Germany), HMDS (1,1,1,3,3,3-
hexamethyldisilazane, Merck, Germany), trifluoroacetic acid (Fluo­
rochem, UK) and BSTFA (N, O-bis (trimethylsilyl) trifluoroacetamide,
Fluorochem, UK) were used in analytical trials for uniformity of content.
2.2. Methods
All measurements and handling of powders, granules or tablets took
place at an ambient temperature of 22 ± 2 ◦ C and a relative humidity of
22 ± 3%. (608 - H1 Hygrometer Testo, China).
2.2.1. Preparation of powder mixtures
Individual substances were consecutively mixed in a cube mixer
KB15S (Erweka, Germany) at 30 rpm, for 10 min in total. Finally,
magnesium stearate was added and mixed for a further 2 min. Three
formulations of powder tableting mixtures F1 to F3 were prepared,
differing according to the concentration of the active pharmaceutical
ingredient Paracetamol: F1 (33% API), F2 (50% API), F3 (66% API). The
composition of powder tableting mixtures is shown in Table 1.
2.2.2. Particle size analysis
The particle size and size distribution of the individual powder
components of the mixtures were analyzed using a Malvern Mastersizer
3000 Laser Diffraction Analyzer (Malvern Instruments, UK) by the dry
cell method. Malvern software was used to determine d10, d50 and d90
values, which are the particle sizes corresponding to 10, 50 and 90% of
the cumulative volume distribution curve, and Sauter diameter d32.
Experiments were repeated 3 times and the average characteristic di­
mensions are shown in Table 1.
2.2.3. Preparation of granules by high shear granulation
In the second step, the powder mixtures were used to prepare
granules. An aqueous solution of polyvinylpyrrolidone, or polethyl­
ethylene glycol respectively, both at concentrations of 1, 3 and 5% (w/
w), were used as binders. The granules GF1 to GF3 were coded in
agreement with the powder mixture composition and the binder used as
illustrated: GF1 PVP 1% meaning the granules prepared from formula­
tion F1 using 1% solution of povidone (Table 2).
High shear granulation of the mixtures was carried out in a batch in
an experimental granulator constructed by the author (Macho et al.,
2020). The device is vertically oriented with a three-blade bottom
driven impeller and a five-blade horizontal chopper. A constant chopper
speed of 1000 rpm was used throughout the granulation process. The
batch of experimental material was 300 g.
Dry mixing of the powder mixture described above was performed
for 2 minfollowed by wetting the mixture, both at an impeller speed of
300 rpm. The amount of binder solution was determined experimentally
to produce granules of about 1–1.5 mm average size: 120 g of a binder
solution was used in the granulation of F1 mixture which represents a
liquid to solid ratio L/S = 40%, 100 g or 40 g of a binder solution was
used for F2 (L/S = 33.3%) or F3 (L/S = 13.3%), respectively. Wet
O. Macho et al. International Journal of Pharmaceutics 608 (2021) 121110

Table 1
Composition of the powder mixtures and characteristic dimensions of the individual components for formulations F1 to F3.
Component Formulation Diameter

F1 F2 F3 d10(μm) d50(μm) d90(μm) d32(μm)

Paracetamol (g) 100 150 200 5.66 35.7 185 13.5

Microcrystalline cellulose (g) 137 87 37 19.8 57.4 132 39.5
Sorbitol (g) 30 30 30 118 232 399 186
Maltitol (g) 30 30 30 5.05 29.6 156 11.1
Magnesium stearate (g) 3 3 3 2.76 10.3 28.6 5.32

PartAn 3D (Macho et al., 2019).

Table 2
Summary of experimental conditions for prepared granules.
2.2.5. Rheological properties
Formulation Coding of Polyethylene glycol Polyvinylpyrrolidone A FT4 powder rheometer (Freeman Technology, UK) was used to
granules solution (%) solution (%)
determine the flow properties of powder mixtures and granules in
F1 GF1 PEG 1 agreement with ASTM-D7891-15,2015 standard (Shi et al., 2018). The
1%*
device consists of different measurement vessels and accessories such as
GF1 PEG 3% 3
GF1 PEG 5% 5
a blade, a vented piston and a shear head.The powder rheometer was
GF1 PVP 1 calibrated for force, torque and height. The powder mixtures F1 to F3
1%* and the prepared granules GF1 to GF3 were analyzed in the following
GF1 PVP 3% 3 tests i) compressibility, ii) shear cell test, iii) stability and variable flow
GF1 PVP 5% 5
rate, and iv) wall friction (Freeman, 2007). The tests were carried out in
F2 GF2 PEG 1
1%* a 50 mm diameter measuring vessel.
GF2 PEG 3% 3
GF2 PEG 5% 5 FT4 compressibility test. The batch of 60 g of powder material or 100 g of
GF2 PVP 1
granules, respectively, was filled into an 85-mL measuring vessel. The
1%*
GF2 PVP 3% 3 powders and granules were filled manually into the vessel. Prior to
GF2 PVP 5% 5 measuring the compressibility, 3 conditioning cycles were performed
F3 GF3 PEG 1% 1 using a 48 mm blade to achieve a homogeneously packed powder bed.
GF3 PEG 3% 3
The pretreated sample was split into a defined volume and the excess
GF3 PEG 5% 5
GF3 PVP 1% 1
material was carefully removed. Then, the mass of sample was recorded.
GF3 PVP 3% 3 Subsequently, the blade was replaced with a vented piston (diameter =
GF3 PVP 5% 5 48 mm) and the normal stress in a range of 0.5 to 15 kPa (9 tests) was
*
“blank” samples used for comparison. Explanation in text. applied to the sample. Compressibility was calculated from the change
in volume of tested sample after compression, expressed as a percentage
(Dudhat et al., 2017). Compressibility measurements were performed 3
massing was run for 2 min at 700 rpm, apart from GF3 PVP samples
times for each sample and the results were interpreted as the mean ±
where 800 rpm was used.
standard deviation.
Using a sieve with a diameter of 2 mm, excess locally formed coarse
granules (agglomerates) were separated immediately after the granu­
lation process. Coarse granules were only found in GF2 granules pre­ Shear test. The batch of 60 g of powder material or 100 g granules was
pared with 5% solution of PEG. The granules were then oven-dried at filled into a measuring vessel and the material was preconditioned by a
60 ◦ C for 24 h. conditioning cycle as decribed above. The shear measurement appa­
In total, 18 types of granules were prepared, i.e., 6 samples for each ratus, consisting of two 85 mL vessels, was the same as for compress­
powder formulation F1 to F3. Two batches of granules prepared from ibility measurement, but it was built with a serrated base to prevent the
powder mixtures F1 and F2 with the lowest concentration of PVP and entire sample from rotating as the blade passed through. Then, the
PEG, both having the mean size of about 1 mm, were used as the “blank” vented piston was used for preconsolidation of the sample bed and the
samples for the comparison reason (Table 2). excess material was removed.
Samples were examined under preconsolidation stress at preshear of
2.2.4. Dynamic image analysis 3, 6 and 9 kPa. The test consists of three steps: 1. shear head pre­
The size distribution of the dried granules was determined using a consolidation, 2. preshear until steady state achieved, and 3. shear test
PartAn 3D particle size and shape analyzer (Microtrac, Germany) by measurement (Freeman et al., 2009). Preshear was applied after each
dynamic image analysis (DIA). The granules were characterized volu­ shear measurement to achieve steady state shear stress and shearing
metrically by digitizing a 3D image of each falling granule particle photo processes. Shear test measurements were repeated 3 times for all
in agreement with ISO standards (13322–2, 9276–6). consolidation stresses. The measurement results were interpreted as
The Area Equivalent Diameter Da (μm) characterising the dimension mean ± standard deviation.
of a granule was calculated by (Eq. (1)): From the normal and shear stress points, a yield locus line was
generated using Mohr circle analysis and parameters such as cohesion,
Da = ((4 × A)/π )0.5 (1) major principal stress MPS (kPa), unconfined yield strength UYS (kPa),
angle of internal friction AIF (◦ ) and effective angle of internal friction
where A is the area of projected image (average from a sequence of
AIFE (◦ ) were derived. The flow function coefficient ffc (-) was calculated
3D images). The width of distribution (span) was estimated by Eq. (2)
according to Eq. (3). (Jenike, 1964).
where d10, d50 and d90 are the particle sizes as explained above.
ff c = MPS/UYS (3)
span = (d90 − d10 )/d50 (2)
Finally, the mean granular sphericity ϕmean was obtained using the Stability and variable flow rate test. Stability and variable flow rate tests

3
O. Macho et al.
were performed using a 160 mL measurement vessel with a serrated base
and an 85 mL split vessel. Prior to the actual test, the material bed was
preconditioned by a blade. This was followed by splitting off the excess
material ensuring an equal volume of all samples examined. The
conditioned bulk density CBD (g/mL) were calculated in regard to the
weight of the sample before and after the splitting off, and the known
vessel volume of 85 mL.
The test consists of 11 cycles. The first seven cycles (stability test) are
accomplished by rotating the blade at 100 mm/s counter-clockwise
when the blade moves from top to bottom, and clockwise when the
blade moves upward. The following four tests were performed at blade
tip speeds of 100, 70, 40 and 10 mm/s, respectively, to evaluate sensi­
tivity to different flow rates.
Changes in torque and force on the moving blade were recorded, and
together with the blade position information, were used to calculate the
flow energy E (mJ) to provide powder movement according to Eq. (4).
∫ H( )
T
E= + F dH
R × tan α
0 the slope of the straight-line portion of the Heckel plot. A is a constant
where T is torque (mN/m), F is axial force (N), R is blade radius
(mm), α is helix angle (◦ ) and H is penetration (mm) (Nan et al., 2017).
Torque and force signals are represented as total flow energy, the energy
required to move the blade through the sample from the top to the
bottom of the powder column. Because the values of torque and force are
constantly changing, it is necessary to calculate the energy for each
small distance travelled. The energy gradient is energy measured for
each millimetre of blade travel. The area under the energy gradient
curve yields a total energy (mJ), which value represents the resistance of
the powder to being made to flow in a dynamic state.
Stability and variable flow rate measurements were performed 3
times with 85 g of the powder sample and 6 times with 140 g of the
granular material. The exception was sample GF3 (the smallest gran­
ules) where 120 g was used.
Some other parameters characterizing the material behavior were
derived from the Stability and Variable Flow Rate tests such as the basic
flowability energy BFE (mJ) which is the energy calculated from the
work that the blade has to perform when passing through the layer of
material to be examined from top to bottom during test No. 7, at a blade
tip speed of 100 mm/s. In order to eliminate differences in densities of
granules and powder mixtures and to compare samples, the BFE value
divided by the weight of the material examined was used (Lu et al.,
2017).
The stability index SI (-), calculated as the ratio between the blade
energy in test No.7 and test No.1, and the specific energy SE (mJ/g) were
estimated. Unlike BFE, this measurement is made by moving the blade of
material upwards in a clockwise direction (Tank et al., 2018). It char­
acterizes the flow of powder material at low load when its value is
mostly affected by cohesion. The specific energy value SE per gram of
material after the splitting process is calculated according to Eq. (5).
(UpEnergyTest 6 + UpEnergyTest 7)/2
SE =
Split Mass
The Flow Rate Index FRI (-) is calculated as the energy ratio of tests
No. 11 and test No. 8; it represents the powder sensitivity to changes in
the tip speed of the blade from 100 to 10 mm/s as it passes down through
the material.
Wall friction. The batch of 60 g of powder material or 100 g granules,
respectively, was filled into an 85-mL measuring vessel. The material
batches were pre-consolidated to 3 kPa and the measurements were
carried out at the normal stress in a range of 3, 2, 1.75, 1.5, 1.25, and 1.0
kPa. Similarly, to the shear cell test, the measurement vessel with a
serrated base was used but a friction disc having a roughness of Ra = 1.2
μm was applied instead of the shear head. By plotting the shear stresses
and the associated normal stresses, a wall friction locus was obtained
International Journal of Pharmaceutics 608 (2021) 121110
and the wall friction angle WFA (◦ ) was determined. The experiments
were repeated 3 times for each sample. The measurement results were
interpreted as mean ± standard deviation.
2.2.6. Single tablet compression
Single tablet compression experiments were performed on a Kistler
NCFN 60 (Kistler Eastern Europe s.r.o.) electromechanical press. The
tablets were compacted in a steel jig formed by a die and a punch with a
diameter of 6 mm loaded to 100 ± 5 mg (Nimbus NBL 254i analytical
balance, readability 0.1 mg, Adam Equipment, UK) of each sample. The
tablets were compacted using six compaction pressures in a range of 50
to 300 MPa, with a punch speed of 5 mm/s. Ten flat faced tablets were
prepared from each sample, examined and analyzed further.
To characterize compressibility of material in the single tablet
compression, in-die Heckel analysis Eq. (6) (Heckel, 1961) was applied.
ln1/(1 − D) = kP + A (6)
(4) where D is the relative density of the compact at pressure P and k is
characterizing the rearrangement of particles. A yield pressure Py = 1/k
(Heckel parameter of plasticity) was estimated.
The relative density D is defined as the ratio between the density of
the compact at pressure P and the true density of the solid particles. The
true density of powder samples was measured in duplicate using
Ultrapyc 1200e helium pycnometer (Quantachrome Ltd, UK). The
pressure P and movement of punches were measured using TraceControl
V1.1.1.4.0 software.
2.2.7. Lab-scale batch compression
Lab-scale batch compression was accomplished using the eccentric
tablet press EP-1 (Erweka, Germany). By the position of the lower
punch, the press was adjusted so that the resulting tablet mass was
approximately 200 mg. The compaction pressure was set to 70 MPa.
Using a compaction rate of 13 tablets per minute, seventy flat faced
tablets of 7 mm diameter were prepared from each powder mixture and
granule samples for further testing.
2.2.8. Tensile strength of tablets
In accordance with the European Pharmacopoeia 10.0, tablet
breaking force, the diameter and the height were determined using an 8
M hardness tester (Dr. Schleuniger Pharmatron). Using Eq. (7), the
tensile strength TS (MPa) of 10 tablets produced by single tablet and lab-
scale batch compression, respectively, was calculated (Fell and Newton,
1970).
TS = 2 × FB /(π × d × h) (7)
where FB (N) is the radial force to break the tablet, d (mm) is the
diameter of the tablet and h (mm) is the height of the tablet.
The tensile strength measurement was carried out immediately after
production and repeated again 24 h after manufacture.
(5)
2.2.9. Uniformity of mass
Ten tablets from each lab-scale batch compression were individually
weighed using a Nimbus NBL 254i analytical scale. Results were
expressed as mean ± standard deviation.
2.2.10. Uniformity of content
A validated analytical procedure was used to estimate the drug
content. The tablet was carefully crushed and 10 mg of this powder were
dissolved in 300 µL of acetonitrile (2 h at 50 ◦ C). Then, 300 µL of HMDS
and 2 µL of trifluoroacetic acid were added to the solution. The solution
was stirred and heated at 50 ◦ C for 30 min and, subsequently, 400 µL of
BSTFA was added.
The sample was centrifuged and the concentration of the drug in
a sample supernatant was measured by flame ionization detector (GC-
FID) gas chromatography under the following conditions: Analysis was
4
O. Macho et al. International Journal of Pharmaceutics 608 (2021) 121110

performed on an Agilent Technologies 6850 Network GC System gas
chromatograph on a SPB-1 column (100% methyl siloxane) 24 m × 250
µm × 0.25 µm. The injected sample volume was 1 μL into the injector
operating in split mode (split ratio 10:1). Hydrogen with constant flow
was used as a carrier gas. Inlet temperature was set to 280 ◦ C. The oven
temperature was set at 60 ◦ C and gradually increased to 310 ◦ C at a rate
of 20 ◦ C/min and held for 4 min.
2.2.11. Data processing
OriginPro 9.0 software (OriginLab Corporation, USA) was used to
process the experimental data. Using this software, statistical regression
analysis of the data and calculation of 95% confidence and prediction
bands were performed.
3. Results and discussion
3.1. Dynamic image analysis of prepared granules
With the increase in the active pharmaceutical ingredient content,
however, a reduction in Avicel® PH 101 content was necessary
(Table 1). While API concentrations of 33 % and 50 % (GF1, GF2)
resulted in similar granule size trends, significant differences were
observed for GF3 with the highest (66%) API content. The lowest Avi­
cel® content resulted in the lowest consumption of granulation liquid to
form granules of the required size of aproximately 1 mm and it was
necessary to use the higher impeller speed (800 rpm). This produced
greater shear stresses which led to the formation of small granules in
GF3 PVP having a low value of the median particle size d50 (0.5–0.59
mm). Even though the sphericity of the granules increased proportion­
ally to binder concentration, the differences were small.
To allow the comparison of samples, the mean size diameter dmean
(mm) was expressed using the following formula (Eq. (8)). Percent sum
in class is related to number of particles.
∑ /
% in class × mid.class size
dmean = 100 (8)
number of classes

The dried granules were analyzed using a PartAn 3D device for Apart from GF3 PVP 5% sample, the span for all granules decreased
particle size, the size distribution and the sphericity. DIA is a technique
that characterizes granules or particles in motion by digitizing photos of
each falling particle (Wei et al., 2020). The characteristic dimensions of
granules GF1 to GF3 in relation to binder concentration are shown in
Fig. 1.
Mean granule size increased with the increase in binder concentra­
tion regardless of its type in all samples. The higher viscosity of higher
concentration binder solution resulted in stronger liquid bridges and
larger granules were obtained. Granules formed by using PEG were
larger in most experiments than granules prepared by using PVP solu­
tions due to its higher viscosity, particularly in the case of the highest
concentration (5 % w/w). Similar results have been reported in the
granulation of micronized paracetamol with povidone solutions (El-
gindy et al., 1988). In the case of F1 granules comprising of the lowest
API content, the same mean granule size of 0.94 mm was detected with a
concentration of 1 % for both binders. These samples were used for
comparison reason with powder mixtures in further investigation as
discussed below.
Except for GF3 PVP, the width of the particle size distribution (span)
of the formed granules decreased with increasing binder concentration
Fig. 2. Dependence between size distribution width (span) and dmean for all 18
as illustrated in Fig. 1. In contrast, granules made from F3 by using PVP
types of granules.
solutions showed the largest span (1.72–2.14).

Fig. 1. Characteristic dimensions, sphericity and span of granules prepared from powder mixtures, depending on the concentration of the granulation liquid. The red
line represents the granule size of 1 mm.

5
O. Macho et al.
in linear proportion with the increasing mean size as illustrated in Fig. 2.
The relationship was pronounced by regression: span = 2.25–1.033 *
dmean with the coefficient of determination R2 = 0.904. The results for
GF3 PVP 5% sample were not included for the wider distribution due to
the larger particles that affected the d90 value.
3.2. Rheology of the samples
To maintain the desired quality of the pharmaceutical product, it is
essential to pre-determine the flowability of particulate matter (Garg
et al., 2018). Especially in direct tableting production, the good flow­
ability of tableting mixtures provides trouble-free manufacture of
products and results in good properties of tablets such as mass unifor­
mity and dose accuracy (Takeuchi et al., 2018). As already mentioned,
rheometer FT4 has found many applications in the analysis of powder
and granular materials in the pharmaceutical industry particularly due
to use of static and dynamic tests.
3.2.1. Compressibility of powder mixtures and granules
A compressibility test measures how the density of a bulk powder
material changes as a function of applied stress. It is defined as the
percentage change in the volume of the sample. Although this test is not
a direct measure of flowability, it can indicate whether the material is
free-flowing or cohesive (Freeman and Fu, 2008). In common, the
cohesive powders show a larger change in the volume (and the density)
than the non-cohesive ones (Tran et al., 2021). The granular material
has generally lower compressibility, higher density and better flow
properties than bulk powder.
The compressibility test with a FT4 rheometer was used for all
powder samples studied in this work. An increase in compressibility
with the increasing paracetamol content was generally detected. For
example, the compressibility of 17.92 %, 22.58 %, and 23.99 % were
observed for powder mixtures F1, F2, and F3, respectively, at the applied
load of 15 kPa. In comparison, the compressibility of pure paracetamol
and Avicel® PH 101 was 36.3% and 15.6%, respectively, at the same
load.
A significant reduction in the compressibility achieved by high shear
granulation is illustrated in Fig. 3. The FT4 compressibility profile of
powder mixtures F1, F2, F3 is compared with the profile of “blank” GF1
granules (Table 2) having the same mean size dmean = 0.94 mm. Five
times lower value in the case of GF1 PEG 1% (3.47 %) and even almost
eight times lower value for GF1 PVP 1% granules (2.32 %) were noted in
contrast to the powder mixtures. This reduction in the compressibility
Fig. 3. The course of the compressibility test depending on the applied normal
stress for powder mixtures (F1, F2, F3) and granules GF1 prepared by the use of
1% solutions of PEG or PVP (n = 3).
6
International Journal of Pharmaceutics 608 (2021) 121110
indicates better flowability of the granules.
3.2.2. Shear test of powder mixtures and granules
During manipulation, the material is generally exposed to various
consolidation stresses that can cause changes in mechanical inter­
particulate forces and its density. To initiate the material flow, it is
necessary to overcome the yield point of the powder bed which is mainly
affected by the material interparticle forces resulting from the particle
size, shape, and surface area as well as the moisture content (Kunnath
et al., 2018). The external forces to which the material is exposed during
handling or processing can be examined with a FT4 rheometer using the
shear cell test. The measurements present data that permit a better un­
derstanding of the material flow characteristics derived by Mohr circle
analysis of the relationship between the normal and shear stresses
(Carson and Wilms, 2006).
Shear properties of the powder mixtures F1 to F3 were evaluated.
The results obtained at consolidation stresses 3, 6, and 9 kPa are shown
in Table 3.
The values of major principal stress (MPS), representing the stress
state during consolidation, had higher values with increasing API con­
tent. MPS values also increased with increasing the consolidation stress.
The angle of internal friction (AIF) characterizes the internal friction
in the shear plane and it is a measure of the ability to withstand shear
stress. It represents the angle between the normal and shear force (the
linearized yield locus). The obtained values of AIF decreased with
increasing API content in the mixtures (Table 3). A higher value means
more pronounced friction connected with the presence of interparticle
interaction (Komínová et al., 2021). As Avicel® PH101 has a higher AIF
value (38.1◦ ) compared to paracetamol (32.6◦ ), this phenomenon was
simply related to its content. Only a mild effect of the used consolidation
stress on the AIF values of powder samples was detected.
The effective angle of internal friction (AIFE) estimated from the line
running through the τ-σ graph origin tangentially to the larger Mohr
stress circle showed a decreasing trend with increasing consolidation
(preshear) stress (Rohilla et al., 2018), (Barletta and Poletto, 2019). The
highest value of AIFE = 46.3◦ was observed at a load of 3 kPa in the case
of formulation F3 (Table 3).
Table 3 summarizes also the values of cohesion estimated from the
intersection of the yield locus with the ordinate (Schulze, 2006). By
increasing the API content in the powder mixture as well as by
increasing consolidation stress, the value of cohesion increased; the
highest cohesion value 1.43 kPa was found for F3 at consolidation stress
of 9 kPa. By the use of a quality by design approach to study flow
behavior of pharmaceutical blends, (Wang et al., 2016b) detected a
linear relationship between cohesion and Unconfined Yield Strength
(UYS). Based on these findings, they proposed classification of the flow
properties of materials according to the value of cohesion. In agreement,
F1 mixture having the lowest content of paracetamol represents easy
flowing material (0.42 kPa < cohesion < 1.05 kPa) while powder
samples F2 at 9 kPa and F3 at 6 and 9 kPa are classified as cohesive
materials (1.05 < cohesion < 2.10).
In common, the material flow properties can also be classified using
the parameters of the flow function ffc generated from shear tests
(Schulze, 2006). At the lowest consolidation stress, the value of the ffc
for all powder mixtures is within the range for cohesive materials (2 <
ffc < 4). At higher consolidation stresses (6 and 9 kPa), F1 formulation
became easy flowing (4 < ffc < 10). F2 formulation remained cohesive at
6 kPa changing to easy flowing (ffc = 4.13) at the highest stress. F3
formulation with the highest paracetamol content was classified as a
fully cohesive material. Similarly, the decreased ffc values in relation to
increasing API content were observed in binary mixtures of paracetamol
and various excipients by (Chen et al., 2019) and (Capece et al., 2016).
However, as the ffc parameter does not include the density of the ma­
terial, some denser powders with lower ffc may flow better because they
are more effectively influenced by gravity.
In addition, the theoretical value of the size of hopper opening able
O. Macho et al. International Journal of Pharmaceutics 608 (2021) 121110

Table 3
Properties of experimental powder mixtures from Shear Cell Test and Stability and Variable Flow Rate. The table shows mean values ± standard deviation (n = 3).
Sample F1 F2 F3

Consolidation stress (kPa) 3 6 9 3 6 9 3 6 9

MPS (kPa) 6.47 ± 0.14 12.33 ± 0.23 18.47 ± 0.21 6.48 ± 0.14 12.8 ± 0.17 18.73 ± 0.15 6.82 ± 0.31 12.73 ± 0.25 18.90 ± 0.43
AIF (◦ ) 36.6 ± 1.5 37.4 ± 0.7 37.4 ± 0.4 36.7 ± 1.3 37.3 ± 0.5 36.4 ± 0.2 35.14 ± 1.00 35.3 ± 0.3 34.8 ± 0.3
AIFE (◦ ) 43.6 ± 0.7 42.2 ± 0.1 42.0 ± 0.2 45.2 ± 0.6 43.9 ± 0.2 42.6 ± 0.2 46.3 ± 0.9 43.8 ± 0.6 42.5 ± 0.5
Cohesion (kPa) 0.44 ± 0.04 0.59 ± 0.09 0.85 ± 0.04 0.53 ± 0.05 0.83 ± 0.07 1.14 ± 0.03 0.71 ± 0.02 1.06 ± 0.06 1.43 ± 0.09
ffc (-) 3.69 ± 0.29 5.26 ± 0.74 5.34 ± 0.18 3.10 ± 0.20 3.82 ± 0.22 4.13 ± 0.08 2.49 ± 0.01 3.12 ± 0.12 3.45 ± 0.15
BFE (mJ/g) 16.28 ± 0.44 13.99 ± 0.19 13.79 ± 0.82
SI (-) 0.94 ± 0.07 0.91 ± 0.06 0.94 ± 0.06
SE (mJ/g) 9.75 ± 0.21 9.96 ± 0.21 10.23 ± 0.50
FRI (-) 1.27 ± 0.10 1.41 ± 0.03 1.43 ± 0.02

F1, F2, F3 - powder mixtures, AIF - angle of internal friction, AIFE - effective angle of internal friction, ffc - flow function parameter, BFE - basic flowability energy, SI -
stability index, SE - specific energy, FRI - flow rate index

to produce arch free flow was calculated using Freeman software. For
axi-symmetric hopper with 20◦ half angle, the detected values of hopper
outlet were 0.47 m (F1), 0.54 m (F2), and 0.74 m for F3 mixture. This
indicates the worsening of flow in context to the increase in API content.
In Fig. 4, the graphical dependence of shear parameters (AIF, AIFE,
cohesion, and UYS) of powder mixtures on MPS is shown. With
increasing the value of MPS, the parameter UYS and cohesion increased,
the values of AIF did not change significantly, on the contrary, the value
of AIFE decreased. As the AIFE is associated with adhesive forces
contribution to the total particle–particle surface contact friction and
interclocking and as this effect decreases with increase in major
consolidation stress, AIFE decreases in agreement (Garg et al., 2018).
Highly compressible and cohesive materials tend to cause problems
when filling the dies as well as when compacting the powder mixtures
into tablets. In order to compare the results of shear test for powder
mixtures and the granules, the “blank” samples GF1 (Table 2) were
selected again. Although the AIF values for the granules GF1 PEG 1%
and GF1 PVP 1% were the same (40.5◦ and 40.7◦ ) at a consolidation
stress of 9 kPa, at lower consolidation stresses they differed similarly to
powder mixtures. The AIF values 35.7◦ and 40.4◦ at 3 kPa and 6 kPa,
respectively, were detected for GF1 PEG 1%, while 41.8◦ and 37.0◦ were
registered for GF1 PVP 1% under the same consolidation stresses. De­
viations resulted from different values of span due to the presence of
polydisperse particles. Easy flowing behaviour was observed for GF1
PEG 1% and GF1 PVP 1% with the cohesion values between 0.03 and
0.25 kPa in the range of used consolidation loads (cohesion < 0.42 -
according to (Wang et al., 2016b) classification). This was also
confirmed by ffc values above 10 (35.31–50.11) for both granule
samples.
Fig. 4. Dependence of shear properties of shear parameters AIF, AIFE, cohesion
and UYS on MPS for powder mixtures F1, F2 and F3 (n = 3).
3.2.3. Evaluation of stability and variable flow rate test
In addition, Table 3 summarizes the results of Stability and variable
flow rate test for powder mixtures F1 to F3. This test is used to describe
the material behaviour at different speeds of the blade and to predict
possible problems due to attrition or segregation. Material is firstly
preconditioned by the passing of a blade through a sample bed to ach­
ieve stability of flow energy; then, 11 measurement cycles (tests) follow
and the energy changes are recorded (Freeman, 2007).
The basic flowability energy (BFE) is mainly influenced by the
compressibility of the material. When moving downwards under a helix
angle of 5◦ , the blade inclination affects the value of the BFE as the blade
pushes the examined material against the bottom of the vessel. If the
material is more compressible, the BFE value is generally higher. In
contrast to cohesion, the BFE parameter decreased with increasing API
content. This is pronounced with the value of BFE = 16.28 mJ/g for F1
mixture as opposed to 13.79 mJ/ g for the more compressible and more
cohesive F3 sample. The API particles form a packing state as the par­
ticles settle on top of each other, resulting in the formation of air
pockets. Due to this fact, the blade passes easily between the particles
which leads to a reduction in the BFE value (Trivedi and Dave, 2014).
Stability index SI (unitless) assesses the instabilities of the flow of the
examined material, whether due to attrition, segregation, moisture ef­
fect or overblending with an additive, e.g., magnesium stearate. For the
powder mixtures, SI was calculated as the ratio between the blade en­
ergy in Test No.7 and Test No.1. The differences between the values
were small. Based on the SI values within the range 0.9 < SI < 1.1
(Table 3), the investigated powder mixtures are characterized as stable,
not prone to particle segregation or attrition. However, it is not possible
to exclude fragmentation of coarse particles during the measurement
that might not be detected by the test. The decrease in SI and BFE values
of powder mixtures compared to pure API was attributed to the presence
of magnesium stearate. (Dudhat et al., 2017) found that the presence of
0.5% magnesium stearate already reduced the BFE values and the spe­
cific energy SE (discussed below) over the entire range of paracetamol
concentrations.
Moving the blade through the material bed upwards in a clockwise
direction, specific energy SE (mJ/g) can be estimated (Tank et al.,
2018). The values characterize the flow of powder at low load and are
closely connected to material cohesion. While the SE values above 10
mJ/g are typical for highly cohesive material, material having 5 < SE <
10 mJ/g is moderately cohesive. As could be seen in Table 3, the values
of SE increased with the increase in content of paracetamol. The results
for SE measurement corresponded well to the aforementioned charac­
terization of powder mixtures based on the ffc and cohesion values. The
value of SE = 10.23 mJ/g detected for F3 shows possible problems in
manufacturing processes, such as die filling.
In order to characterize powder sensitivity to changes in the tip speed
of the blade, the flow rate index FRI (unitless) is estimated. At lower
rotation speeds, the energy that the blade has to expend to pass through
the material increases. Generally, the values FRI > 3 identify higher

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O. Macho et al. International Journal of Pharmaceutics 608 (2021) 121110

material cohesion while values FRI < 1 are typical for powders con­
taining flow enhancers (Leturia et al., 2014). According to the FRI
values, all examined powder samples had average flow rate sensitivity
(Table 3). Similarly, to SE and cohesion results, FRI increased with
increasing API content. The cohesive powders are more compressible
due to the presence of a higher air content. Due to the air being easily
released around the blade, the powder bed becomes stiffer and more
resistant to flow (Freeman, 2007).
The results of Stability and variable flow rate test for granules GF1 to
GF3 are shown in Table 4 except for GF3 PEG granules showing similar
results to GF1 PVP due to the similar size distribution, and GF2 PEG 5%
with the largest granule size dmean = 1.6 mm.
The values of the BFE parameter of granules were greater than those
registered for the powder mixtures (Table 3). This phenomenon was
caused by an increase in conditioned bulk density (CBD, Table 4). When
compared with the F1 to F3 mixtures (CBD in the range of 0.412–0.432
g/mL), the blade movement was hindered by a particle bed having a
higher bulk density. The lowest CBD values were observed for GF3
granules which were also characterised with a low value of BFE. As the Fig. 5. Comparison of total energy during stability (1–7) and variable flow rate
BFE generally decreases with the decrease in the mean size of granules (8–11) tests for powder mixtures (F1, F2, F3), and granules GF3 formed with 1,
(Mohylyuk et al., 2019), the lowest value 16.84 mJ/g was found at GF3 3 and 5% solution of PVP. (n = 3 for powder mixtures, n = 6 for granules). Total
PVP 3% with the smallest granule size. Simultaneously, the particle size energy - area under the energy gradient curve yields.
influenced the BFE standard deviations (SD) at repeated measurements
as illustrated with the highest observed SD value of 10.71 mJ/g for the per mm of blade travel) and resistance of the powder material can be
largest granules (dmean = 1.42 mm) GF2 PVP 5%. The BFE results are estimated (Freeman et al., 2016). In contrast to powder mixtures F1 to
similar to the study of (Narang et al., 2016) who investigated granules F3, the increase in energy is visible for the GF3 that shows unstable flow
prepared with the use of 1, 3 and 5% hydroxypropyl cellulose solutions. of granular material, which would result in segregation during transport
The comparison of the total flow energy (mJ) that the blade had to and handling.
expend when passing through the bed of material during the first seven Stability index SI values were >1 for all granule samples; the highest
stability and variable flow rate tests is shown in Fig. 5 for powder average SI value 2.88 was observed for GF2 PVP 5% granules. This
mixtures and granules GF3 PVP (the smallest particle size). Measuring phenomenon was caused by particle segregation; the larger granules
the values of torque and force required, the energy gradient (the energy move upwards when the blade forces its way through the bed.
Conversely, the “blank” granules GF1 PVP 1% and GF1 PEG 1% showed
the same SI value. This resulted in the partial conclusion that the SI
Table 4 parameter increases with the mean size of the granules. The relationship
Stability and variable flow rate test parameters for selected granules. The table between specific energy SE and particle size distribution (span) is
shows mean values ± standard deviation (n = 6).
illustrated in Fig. 6. The negative linear proportion is pronounced by
Form. Granulation BFE CBD (g/ SI (-) FRI (-) SE (mJ/ coefficient of determination R2 = 0.85. As shown in a small inserted
liquid (mJ/g) mL) g) graph in contrast, SE increased with the mean particle size (dmean). The
GF1 PEG1% 21.27 ± 0.819 ± 1.47 ± 0.72 ± 7.77 ± smallest values of the SE parameter were found in the GF3 with the
0.16 0.006 0.06 0.05 1.01 smallest granules.
PEG3% 17.11 ± 0.777 1.18 ± 0.66 ± 7.30 ±
±
As summarized in Table 4, the values of SE > 10 mJ/g were mainly
1.09 0.007 0.24 0.19 0.24
PEG5% 26.59 ± 0.775 ± 1.57 ± 1.19 ± 11.09 ± registered for larger granules prepared with the highest concentration of
2.40 0.006 0.40 0.17 0.97 binder. In upward stability tests, the blade overcomes larger particles
PVP1% 25.82 ± 0.773 ± 1.47 ± 1.26 ± 11.85 ±
1.09 0.000 0.09 0.37 1.74
PVP3% 23.56 ± 0.764 ± 2.27 ± 1.02 ± 9.33 ±
2.23 0.011 0.34 0.08 1.79
PVP5% 21.50 ± 0.770 ± 1.93 ± 1.20 ± 11.93 ±
2.91 0.011 0.35 0.13 0.66
GF2 PEG1% 25.27 ± 0.699 ± 1.76 ± 1.02 ± 8.72 ±
2.64 0.006 0.18 0.08 1.14
PEG3% 31.07 ± 0.678 ± 2.20 ± 1.13 ± 13.11 ±
5.08 0.011 0.09 0.02 3.27
PVP1% 35.44 ± 0.721 ± 2.18 ± 0.94 ± 11.34 ±
8.50 0.010 0.22 0.02 1.55
PVP3% 28.89 ± 0.711 ± 2.29 ± 1.17 ± 11.79 ±
5.64 0.010 0.52 0.29 3.13
PVP5% 32.75 ± 0.707 ± 2.88 ± 1.14 ± 14.27 ±
10.71 0.010 1.21 0.17 1.17
GF3 PVP1% 18.47 ± 0.630 ± 1.57 ± 1.03 ± 6.49 ±
1.40 0.021 0.16 0.00 0.19
PVP3% 16.84 ± 0.623 ± 1.68 ± 1.04 ± 6.31 ±
1.54 0.016 0.11 0.04 0.47
PVP5% 17.10 ± 0.626 ± 1.39 ± 1.05 ± 6.29 ±
1.54 0.025 0.03 0.05 0.30

GF1, GF2, GF3 – granules prepared from powder mixtures F1 to F3, PEG -
polyethylene glycol, PVP - polyvinylpyrrolidone, BFE - basic flowability energy,
CBD - conditioned bulk density, FRI - flow rate index, SI - stability index, SE - Fig. 6. Dependence of the SE parameter on the span value and the dmean size of
specific energy the granules for all analyzed granule samples (n = 6).

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O. Macho et al. International Journal of Pharmaceutics 608 (2021) 121110

which is more energy consuming. Sample GF3 PVP 5% was the excep­
tion as these granules were the smallest. Although the SE parameter is a
representation of flowability for non-constrained powder such as during
low-speed mixing or low-pressure filling, larger granules with larger
span can be affected by the segregation process as mentioned above.
The FRI values showing sensitivity to blade speed change were lower
for all granules when compared to those observed for powder mixtures.
This reflected the lower cohesion of the granules discussed above. As
generally cohesive powders are more sensitive to changes in flow rate
(Leturia et al., 2014), the granular material shows lower sensitivity. FRI
values < 1.5 reflect materials containing, for example, larger particles or
particles surface-treated in order to improve the flow properties.

3.2.4. Evaluation of wall friction

The measurement of wall friction characterizes the relationship of
frictional forces between the particulate material and the surface of the
container in which the material is stored or processed. The wall friction
head of FT4 rheometer induces the required normal stress in the powder
bed and then slowly shifts to induce shear stresses.
The wall friction angle (WFA) of the investigated materials was
measured using a stainless steel friction disc with a roughness of Ra =
1.2 μm. For powder mixtures F1 to F3, WFA decreased with the increase
in the API content (26.37◦ , 24.03◦ , and 23.23◦ , respectively). This
phenomenon indicates lower resistance and adhesion between the ma­
terial and the friction disc due to the higher paracetamol content. Ac­
cording to the WFA values, all mixtures can be classified as moderately
flowable. In agreement with (Søgaard et al., 2014) study, the WFA value
of granules decreased with increasing particle size of materials. For GF1
PEG 1% granules with dmean = 0.94 mm, the WFA value was = 23.27◦ .
3.3. Single tablet compression
Preparation of tablets includes two primary steps: filling a die with
material, and the compaction. During the second step, a compact having
suitable properties such as mechanical resistance and tensile strength
should be obtained. As the quality of the final product is highly sensitive
to manufacturing scale (Ghazi et al., 2019), tablets were prepared by
two different methods: i) a single tablet compression method illustrating
production of one tablet and ii) a lab-scale compression method illus­
trating small scale, partially continuous production.
Direct compaction of powder tableting mixtures presents a relatively
fast and efficient manufacturing process. However, poorly compactible
materials, such as e.g. those containing paracetamol (Taipale-Kovalai­
nen et al., 2018), can produce serious problems. Compressibility of the
powder mixtures F1 to F3 and the selected granules, GF1 and GF2, was
first investigated in the single tablet compression experiment using
pressures in a range between 50 and 300 MPa.
Fig. 7. Heckel plot for F1 powder mixture and granules GF1 PVP 1% and GF1
PEG 1% (only one curve from each compacted material was selected
for clarity).
during the relaxation phase of the compaction process, higher tensile
strengths of tablets can be measured (Davis et al., 2018).
However, it is difficult to completely separate the contributions of
plastic and elastic deformation mechanisms to the strength of a compact;
the strength is mainly influenced by the formation of physical bonds
between particles due to plastic deformation (Hiestand, 1997). Using
Eq. (6), yield pressures Py = 1/k (Heckel parameter of plasticity)
reflecting the particle deformability during the compression were
calculated. In Fig. 8, the results for above mentioned samples F1, F2,
GF1 PVP 1%, and GF1 PEG 1% are shown. Samples F3 were not analyzed
due to significant lamination over the entire range of compaction pres­
sures (Fig. 9a). The Py values increased with compaction pressure. As the
electromechanical press in single tablet compression allows the regis­
tration of all results even though no tablets of sufficient hardness could
be prepared, the results of the F2 mixture compaction at pressures of 50
and 100 MPa are shown.
A lower yield pressure generally indicates a higher plasticity of the
material (Sun and Grant, 2001). In agreement with generally accepted
plasticity of MCC (Desai et al., 2018), the lower Py value was observed
for powder mixture F1 with a higher MCC content (i.e. lower amount of
paracetamol) in comparison to F2 mixture. The exception is only at the
highest compaction pressures when the F1 mixture became

3.3.1. Compressibility study by Heckel analysis

Three phases of the compaction process are generally referred to: i)
an initial stage of particle rearrangement, ii) plastic deformation and
fragmentation, and iii) elastic deformation. The consolidation mecha­
nisms of powder and granule samples were studied in this work by in-die
Heckel analysis (Heckel, 1961).
The differences between the Heckel curve observed for F1 and the
GF1 PVP 1% and GF1 PEG 1% “blank” granules are illustrated in Fig. 7.
In general, the significantly easier rearrangement of particles (detail in
inserted graph) and transition to the linear region of plastic deformation
are visible for the powder mixtures. Contrarily, the granular material
underwent plastic deformation easily and rapidly. During the
compression, the granules were fractured into small ones which facili­
tated further rearrangement and, moreover, this resulted in a better
formation of physical bonds between the particles leading to an increase
in the tablet strength as will be discussed later. In addition, the differ­
ences in area of elastic deformations for the powder mixtures and Fig. 8. Comparison of yield pressure for powder mixtures (F1, F2) and granules
granules were observed in Fig. 7. If elastic deformations are not released (GF1, GF2) prepared with 1% solutions of PEG and PVP, respectively (n = 10).

9
O. Macho et al.
Fig. 9. Tabletability of powder mixtures and granules, a-powder mixtures (F1
to F3), b-comparison of F1 and granules GF1 prepared by 1% solutions of PVP
and PEG, c- comparison of F2 and granules GF2 prepared by 1 % PVP and PEG
(n = 10).
overcompressed as will be discussed in Chapter – 3.4.2.
The lower Py values were generally registered for granules showing
higher plasticity (Sun and Grant, 2001). At low compaction pressure (50
MPa), the differences in Py were not observable but they reached
considerable levels at compression pressures above 100 MPa. The values
of Py decrease with the increasing size of the compressed particles
(Cabiscol et al., 2020). The Py values were lower for the PVP granules
than those produced by PEG solutions in most experiments. The fluc­
tuation in Py values resulted from the actual differences in the sphericity
and width of the distribution of the granules prepared (Veronica et al.,
2018).
3.3.2. Tabletability of powder mixtures and granules
Tablets should have a suitable mechanical resistance to withstand
subsequent processing, transport and handling by the patients (Reynolds
et al., 2017). Two tests are recommended to determine the mechanical
strength of tablets, namely the friability of uncoated tablets and the
resistance to crushing based on the diametral compression test (Juban
et al., 2015). The latter was used in this study; the breaking force was
measured immediately after production and the tensile strength of
tablets was calculated using Eq. (7). The tensile strength of tablets
prepared from granules was estimated immediately after production and
repeated again after 24 h. As the changes in tensile strengths after 24 h
were below 0.5%, the immediatelly estimated values are used instead.
The tensile strengths (MPa) obtained are illustrated in Fig. 9 for
powder mixtures F1 - F3; the results for F1 and F2 are also compared to
granules GF1 or GF2 prepared with 1% solutions of PEG and PVP,
respectively.
10
International Journal of Pharmaceutics 608 (2021) 121110
In the powder mixtures F1 - F3, the compaction process was influ­
enced by the API content. During compaction of the powder tableting
mixture F1 (the lowest amount of paracetamol), the tensile strength of
the tablets increased with increasing compaction pressure up to 250
MPa, when the tablet strength value was 1.75 MPa (Fig. 9a). By further
increasing the compaction pressure, overcompaction occurred reducing
the tensile strength. Similar overcompaction at higher compaction
pressures has been reported by (Li et al., 2019), and (Cheng et al., 2020).
As mentioned above, it was not possible to produce tablets up to a
compaction pressure of 150 MPa from the F2 formulation (50 % of
paracetamol) and the low tensile strength value of 0.55 MPa was
detected even at a compaction pressure of 300 MPa. Compaction of F3
mixture (highest content of paracetamol) was accompanied by a sig­
nificant lamination of tablets over the entire range of compaction
pressures (Fig. 9a) and such tablets were too brittle for hardness testing.
Paracetamol is widely known to be elastic in compression behaviour
thus cause capping in tabletting (Anuar and Briscoe, 2010) and our re­
sults were consistent with this. The tablets showing elastic expansion
can be easily damaged during ejection.
In Fig. 9b and 9c, the results for granules GF1 and GF2 prepared
using 1% solutions of PVP and PEG are shown. The processing of the
material by wet granulation did not show a significant influence on the
tabletability of formulation F1. However, the overcompaction of the
sample at compaction pressures of 300 MPa was avoided. The tensile
strength of tablets made with GF1 PVP 1% was higher (2.46 MPa) than
for GF1 PEG 1 % (1.61 MPa) at 300 MPa which is the result of larger
particle size and lower value of Py for GF1 PVP granules.
The positive effect of the granulation on the tabletability and tensile
strength of the tablets was observable over the entire range of
compaction pressures for GF2 when compared with the F2 mixture.
Material was already compressible at a compaction pressure of 50 MPa.
The tensile strength of GF2 PVP 1% tablets was higher than of GF2 PEG
1% and similar results were detected for other used concentrations of
binders.
The results are consistent with the Heckel analysis decribed above.
The lower tensile strength of tablets corresponded to the higher Py
values for powder materials. This phenomenon was caused by the fact
that powder materials were able to achieve greater packing in the die
and hence, exhibited lower movement as compaction pressure was
applied (Patel et al., 2006). The increase in the tensile strength is
generally due to the plastic deformation and formation of interparticle
bonds. This was confirmed for PVP granules. The Heckel plot showed
significant differences in the compressibility of powder mixtures and
granular materials due to fragmentation, attrition and particle rear­
rangement. A more detailed description of the relationship between
tensile strength and the Py parameter can be found in the work (Ghori,
2016).
3.4. Lab-scale batch compression
In order to illustrate batch tablet production, the behaviour of the
tabletting material during the lab-scale compression was monitored
using an eccentric Erweka EP1 automatic press. For the powder mixtures
F1 - F3, some problems were anticipated due to their cohesive behav­
iour, the high compressibility and poor flow properties (Table 3). As
expected, fast jamming occured when filling the die with the F1
formulation. Even though this powder mixture showed the lowest
cohesion value and a moderate value of WFA, the formation of an arch in
the feeding hopper (Fig. 10a) and the shoe (Fig. 10b) was observed.
Similar behaviour was observed in F2 and F3. As only a few tablets could
be formed from each powder sample they were not analyzed further.
The better flow properties of the GF1 to GF3 granules positively
affected the batch compression and confirmed the general importance of
the high shear granulation process. In addition to the HSG, however, it
should be mentioned that direct compression of paracetamol can be
done if the formulation consists of suitable directly compressible grades
O. Macho et al.
Fig. 10. Arching of F1 mixture in lab-scale batch compression with an eccentric
tablet machine: a - top view of the feeding hopper, b - bottom view of the wiper
shoe of the tablet press.
of excipients that are both fragmenting and plastic.
The experiments with powder material showed significant differ­
ences between single tablet and lab-scale batch compression. Since the
material was directly poured into the die during single tablet (design)
compression, the inapropriate flow properties of samples influenced the
compaction process only occasionally such as e.g., at higher concen­
trations of API (lamination). Contrarily, good flow properties are a key
parameter for the proper operation of the continuous tableting process.
(Wu et al., 2003) found that the level of die filling can also be affected by
the speed of filling itself. In order to evaluate the properties of samples,
the same filling speed was used in all compaction experiments. The re­
sults obtained at a compaction pressure of 70 MPa are shown in Fig. 11.
The values increased with the content of binder used in the HSG
similarly to the work (Autamashih et al., 2011). In the compaction of
GF1, a higher tensile strength was observed for tablets obtained for GF1
PEG compared to GF1 PVP granules. This is illustrated by comparing
“blank” GF1 PEG 1% granules (0.74 MPa) and GF1 PVP 1% granules
Fig. 11. Tensile strength of lab-scale batch compacted tablets produced from
selected granules GF1, GF2, and GF3 at compaction pressure of 70 MPa (n
= 10).
11
International Journal of Pharmaceutics 608 (2021) 121110
(0.54 MPa) having the same mean particle size dmean = 0.94 mm. In
contrast, the same tablet tensile strengths 1.06 MPa and 1.09 MPa were
noted for GF2 PEG 1% and GF2 PVP 1%, respectively. Higher tensile
strength in tablets of GF2 PVP sample was also recorded in single tablet
compression (Fig. 9).
As can be seen in Fig. 11, the highest tensile strength was detected at
GF3 PVP 5% granules (2.029 MPa). Eichie and Kudehinbu, 2009
observed that tensile strength increases with the decrease in granule
size. Our results were in good agreement as the particle size dmean =
0.63 mm was the smallest out of all granule samples.
The tensile strength of the tablets in lab-scale batch compression was
mainly influenced by the CBD values. In Fig. 12, the linear relationship
between CBD of granules GF1 to GF3 and tablet tensile strength char­
acterized with the coefficient of determination R2 = 0.86 is illustrated.
As CBD is related to particle size, it confirmed again that GF3 samples
with the smallest particles (Fig. 1) and lowest CBD values (Table 4)
showed higher tensile strength values. In contrast, GF1 samples with
higher CBD values achieved lower tensile strength values.
Apart from dmean, it has to be noted, that the particle size distribution
influenced the tensile strength values as well. Tablets compacted from
the small granules (GF3) with the wider size distribution showed the
higher values of tensile strength at the same compaction pressures as
these small granules not only filled the die space quickly, but also easily
penetrated into interparticle voids. However, this observation could not
be applied to all experiments.
3.4.1. Mass and content uniformity of lab-scale batch produced tablets
Ten tablets of a targeted mass of 200 mg, were weighed and the mean
and standard deviations were expressed. A smallest difference in mass
uniformity (0.39 %) was detected for tablets produced from GF1 PEG 3%
with lowest CBD. With the increasing span of granules, the mass uni­
formity of tablets decreased; the largest deviations (2.07 %) were
detected with tablets prepared from GF3 PVP 5% granules.
Lab-scale batch prepared tablets from GF1 granules with a target
value 33 % of paracetamol were also analyzed for content uniformity by
gas chromatography. (Muthancheri and Ramachandran, 2020) found
that the size and size distribution of the granules, significantly affected
content uniformity of paracetamol tablets. Our results were consistent
with this as uniformity in API content decreased with increasing dmean of
granules. The smallest differences in API content (0.2 %) were detected
for both granules GF1 PVP 1% and GF1 PVP 3% contrary to GF1 PEG 1%
and GF1 PEG 3% granules showing 2.7% deviation in API content. In
contrast, the largest deviations 5.99 % and 5.77% were registerred for
GF1 PEG 5% granules and GF1 PVP 5%, respectively.
Fig. 12. Dependence of tensile strength on CBD in lab-scale batch compression
of granules GF1, GF2 and GF3.
O. Macho et al.
4. Conclusions
Good flow properties of particulate matter are important to avoid
problems in routine tablet production. Based on the results of dynamic
image analysis as well as the static and dynamic tests available with
powder rheometer, this article describes the flow properties,
compressibility and tabletability of three powder tableting mixtures
containing various concentrations of paracetamol (33–50 − 66 %) and
the equivalent granules prepared by high shear granulation. Despite the
addition of magnesium stearate, poor flow properties associated with
high compressibility and cohesion were observed for powder mixtures.
The higher the content of API the worse properties were detected. This
negatively influenced both methods of tablet production leading to
overcompaction or lamination in the single tablet compression or to
arching and blockage of the feeding hopper in the lab-scale batch
compression with an eccentric tablet machine.
Using high shear granulation, granulometric and flow properties of
mixtures were positively affected. Even though rheology parameters
worsened generally with the increasing in API content, the reduction in
compressibility and cohesivity resulted in trouble-free single tablet as
well as lab-scale batch tablet production for all formulations using
compaction pressures in a range of 50–300 MPa. The differences be­
tween powder mixtures and granules were demonstrated by in die
Heckel analysis. The lower Py values registered for granules showed
their higher plasticity, particularly at compaction pressures above 100
MPa.
The results for granules were interpreted with respect to the particle
morphology obtained from dynamic image analysis. The granule size
increased proportionally with the increase in binder (either PEG or PVP)
concentration in a range of 1–5 % while the width of sample particle size
distribution (span) decreased. Dependencies were found between the
parameters obtained from the DIA and the data from the powder
rheometer, as well as the data from the rheometer on the compression
parameters. A linear relationship was detected between the span of
granules and the specific energy (R2 = 0.85). This parameter charac­
terizes the flow of material at low load such as e.g., die filling; the
smaller the granules the smaller the values of the SE were observed. In
agreement with the increasing particle size, the Py values obtained by
Heckel analysis were mostly lower for the PVP granules than for those
produced by PEG solutions. A linear relationship with the coefficient of
determination R2 of 0.86 was displayed between the tensile strength of
the tablets at lab-scale batch compression and CBD values of GF1 to GF3
granules. This also clearly demonstrated the influence of particle size;
GF3 samples with the lowest CBD values and smallest particle size
showed the higher tensile strength values as opposed to GF1 granules
with higher CBD and lower tensile strength values. The importance of
particle size was finally demonstrated during the evaluation of the mass
and content uniformity. With an increase in the span of granules, the
mass uniformity of tablets decreased, and simultaneously with an in­
crease in the size of granules, uniformity in content decreased.
CRediT authorship contribution statement
Oliver Macho: Conceptualization, Writing – original draft, Investi­
gation, Methodology. Ľudmila Gabrišová: Visualization, Investigation,
Conceptualization. Jana Brokešová: Data curation, Investigation.
Petra Svačinová: Writing – review & editing, Methodology. Jitka
Mužíková: Writing – review & editing, Methodology. Paulína Galbavá:
Data curation, Investigation. Jaroslav Blaško: Data curation, Formal
analysis. Zdenka Šklubalová: Supervision, Conceptualization, Writing
– review & editing.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
12
International Journal of Pharmaceutics 608 (2021) 121110
the work reported in this paper.
Acknowledgements
The authors would like to thank IMCD Czech Republic, s.r.o. Prague,
for their cooperation in the research and Grant Scheme to support
excellent teams of young researchers under the conditions of the Slovak
University of Technology in Bratislava.
Funding
This work was supported by the Funding Agency of Charles Uni­
versity [Grant No. 268120/2020; Grant No. SVV 260 547]; European
Regional Development Fund [ITMS 26240220084], [313021X329];
Slovak Research and Development Agency [APVV-18-0348], [APVV-18-
0282], [KEGA 016STU-4/2019, KEGA 036STU-4/2020].
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