Pevnost a oděr jsou důležitými vlastnostmi pelet, protože umožňují předpovídat jejich chování v průběhu technologických procesů, např. při filmovém obalování, plnění do tvrdých želatinových tobolek nebo při lisování do tablet. V současné době lékopisy neuvádějí žádné metody k testování uvedených vlastností u pelet a v praxi se používají metody odvozené z metod doporučených pro hodnocení tablet. Ke stanovení oděru pelet slouží různé přístroje a aplikuje se řada metod, které se navíc liší i podmínkami testů. Pro vyhodnocení vlivu rozdílných podmínek metody na hodnoty oděru pelet se pro tento experiment vybraly pelety různé pevnosti a složení, připravené několika technologiemi. Oděr pelet se testoval vždy ve stejném zařízení za odlišných podmínek, zkoušené množství vzorků a celkový počet otáček však zůstávaly konstantní. Všechny vzorky měly také podobný obsah vlhkosti. Vzhledem k tomu, že se hodnoty oděru u téhož vzorku často významně lišily, je bezpodmínečně důležité u zvolené metody dodržovat vždy stejné podmínky k dosažení reprodukovatelných a srovnatelných výsledků. Experiment naznačil, že oděr pelet je ovlivněn nejen jejich složením ale také způsobem výroby.
Klíčová slova: pelety – pevnost – oděr – metody hodnocení – podmínky testování
E. Gryczová; K. Dvořáčková; M. Rabišková
Authors place of work:
University of Veterinary and Pharmaceutical Brno, Faculty of Pharmacy, Department of Pharmaceutics Sciences, Czech Republic
Published in the journal:
Čes. slov. Farm., 2009; 58, 9-13
Pellet friability and hardness are important particle characteristics as they predict pellet behavior during technological processes such as film coating, filling into hard gelatin capsules or compressing into tablets. At present no methods for testing of these pellet properties are present in pharmacopoeias and various methods adapted from tablet evaluation are used. A number of methods and different equipment are used to determine pellet friability. These methods in addition differ also in the testing conditions. Therefore pellets of different hardness and composition were chosen on purpose for this experiment to show the influence of method variables on the friability of brittle and hard pellets prepared by different techniques. Pellet friability was tested in the same equipment under different conditions, but always with the equal amount of sample and equal total number of revolutions. All the samples exhibited also similar residue moisture content. As different friability values were obtained for the same sample under different testing conditions it is necessary to pay attention to the method used and its parameters. This experiment indicates that pellet friability is influenced not only by pellet composition but also by the technique of their manufacture.
Pellets are small spherical particles used for oral
application; their diameter for pharmaceutical purposes lies usually
in the range of 0.5–2.0 mm. As multiparticulates, i.e. higher
number of particulate drug units in one dose, they exhibit several
advantages comparing to single unit dosage forms such as tablets. In
pharmacotherapy, they offer the drug delivery independent on the
stomach emptying, a reduction of gastrointestinal tract irritation
and minimizing of side effects. Flexibility in dosage form design,
possible combination of several drugs in one dose, improved stability
and easy coating due to pellet spherical shape belong among their
advantages in technology. Therefore pellets are very often used for
controlled drug release preparations, i.e. they undergo subsequent
processes such as coating, filling into hard gelatin capsules or
compressing into tablets. Thus their mechanical properties especially
pellet hardness and friability are very important parameters. In
fluid bed film coating the friability of pellet cores can
significantly influence the coating quality. A high amount of
attrition of the core material during the coating procedure could
modify drug release behavior due to the incorporation of small
particles into the film coating 1).
For this and above mentioned reasons mechanical pellet properties
should be evaluated using appropriate well defined methods.
Pellet hardness is usually measured using tablet
strength testers equipped with a cell for pellet evaluation. However
it is significantly dependent on pellet diameter, composition and
manufacturing process 2).
Hardness is characterized as a resistance against the crushing under
defined conditions. It is measured in a tester consisting of two
clips the sample is inserted in. The clips are moving against each
other and the force when the sample breaks is registered
3). Hardness is determined either in
Newtons or kilograms: 1N = 9.81 kg.
To compare the hardness of tablets differing in shape
there exist formulas describing their diameter and thickness
4). Similar formula can be used also for
is the tensile strength, F
is the crushing force, r
is the pellet diameter. The unit of δf(s)
Pellet friability can be determined by a number of
different methods using various equipments. Widely used are rotating
drums like friability testing apparatus for tablets, e.g. Erweka 7,
8) or Roche 9–12)
Friabilator. Due to the electrostatic charge and low weight of
pellets providing insufficient mechanical stress during these tests,
their stainless steel variation and the addition of glass or steel
balls are used. However the friability conditions among these methods
differ significantly, for instance the number of balls from 10 11)
to 200 7, 12),
their material, i.e. glass 7, 9–12)
or steel 8), the
amount of pellets 5 g 9, 11)
or 10 g 7, 8, 10, 12),
testing time from 3 8)
to 10 7, 10,12)
minutes, and rotating speed of 10 8),
25 12) or 36 9)
rpm. Another group of tests is based on the use of a Turbula blender
13, 14) or
horizontal shakers 15, 16).
All these described methods work in closed systems. Thus the
attrition remains in the apparatus and can get into a contact with
the surface of pellets.
As friability testing apparatus should simulate the
conditions the product will be exposed to in the production process
later on, e.g. during coating or drying processes in fluid bed
devices an open system would be more appropriate as the attrition is
removed immediately from the tested system 17,
Friability is characterized as the weight loss of a
sample (%) 17),
the mean pellet diameter reduction (%) 19,20)
or the difference in areas under the curve of pellet size
distribution before and after the friability testing 21).
Limit value of pellet friability should correspond to
their intended use 21),
for instance for pellets proposed for subsequent coating value lower
than 1.7% is recommended 22).
In this experimental study pellet hardness and
friability were tested, and the influence of pellet composition,
preparation process and variables of friability test on pellet
mechanical properties was observed.
In this experiment, pellets of different composition
prepared using various pelletization techniques were chosen (Table
1). Freely soluble diltiazem hydrochloride (DHCl, kindly donated by
Zentiva, Czech Republic) or sparingly soluble diclofenac sodium (DNa,
Amoli Organics, Mumbai, India) were used as model drugs.
Microcrystalline cellulose (MCC, Avicel®
PH 101, Mingtai Chemical Co., Ltd., Taiwan), lactose monohydrate
(Cerapharm, Vienna, Austria) and povidone (PVP, Kollidon®
25, BASF, Germany) were excipients, and Celphere®
(Asahi Kasei Kogyo, Japan) were used as inactive cores. All
substances were of pharmaceutical grade (Ph.Bs. 2005; Ph. Eur. IV);
other materials used for pellet evaluation were of analytical purity.
Pellets were prepared either by a layering technique or
by an agglomeration in a Rotoprocessor (Multiprocessor MP 1,
Aeromatic Fielder, Switzerland). For layering, MCC inactive cores
305) or lactose/MCC cores prepared in our laboratory were used as
starters. Lactose/MCC cores were prepared as follows: 350 g of MCC
and 650 g of lactose were mixed for 5 min in a Stephan mixer (UMC 5,
Germany). One kilogram of powder blend was loaded into the inner bowl
of the Rotoprocessor and water was sprayed into the container at the
optimal, experimentally determined rate 23).
Once all the water was sprayed, spheronization was performed for 2
min. After completion of the pellet formation, the pellets were dried
at 50 °C by lifting the inner wall of Rotoprocessor. Required
pellet size fractions, i.e. 0.5–0.8 mm and 0.8–1.0 mm, were
separated on sieves of appropriate apertures. To prepare the active
pellets of samples 1 and 3, concentrated solution (i.e. 50% w/w) of
DHCl in purified water with PVP was sprayed onto the smaller starters
surface in a fluid bed unit equipped with a Wurster column
(Multiprocessor MP 1, Aeromatic Fielder, Switzerland) until the
theoretical drug amount reached 50% of the pellet weight. Pellets
were dried in the same equipment and stored in plastic bags at room
temperature for further evaluation. The other pellet samples, i.e.
samples 2 and 5 were prepared in a Rotoprocessor by wetting and
spheronizing the homogenized powder mixture (Table 1) as described
above. Purified water was used as the wetting agent. Celphere®
(CP 507) produced commercially were used as sample 4 for mechanical
pellet properties comparison.
Particle size and size distribution of both, starters
and prepared pellets, were determined by a sieve analysis for each
sample. The set of stainless steel sieves with apertures in the range
of 0.5–1.0 mm and a sieve shaker (type AS 200, Retsch, Germany)
were used. Particles smaller than 0.5 mm were considered as a dust
and particles bigger than 1.0 mm (for sample 1 bigger than 0.8 mm) as
agglomerates and were excluded from the total yield. Selected pellet
fractions were used for further evaluation.
The particle shape and internal structure were examined
using a JEOL JSM-6700F scanning electron microscope (JEOL Ltd.,
Japan). Samples were mounted on a cylindrical stub using a
double-sided sticky tape. The samples were coated with an approx. 70
nm thick gold layer in a SCD 030 sputter coater (Balzers Union Ltd.,
Balzers, Liechtenstein) and observed under the microscope operating
at 5.0 kV.
The hardness of used starters and prepared pellets was
tested on the C 50 Tablet Hardness Tester (Engineering Systems,
England) equipped with a C5 cell for pellet evaluation. The hardness
of ten randomly selected particles of each sample was evaluated.
For friability testing, 10 g of dust free particles
(pellets or starters) were precisely weighed, put into the
friabilator Roche (type TAR 10, Erweka, Germany) with stainless steel
drum along with 200, 100 or 10 pieces of 4 mm glass beads,
respectively, and rotated for 10 or 5.5 minutes at 20 or 36 rpm. The
experimental conditions are described in Table 2. Particles smaller
than 0.25 mm were regarded as the attrition. The friability was
expressed as a percentage of the weight loss after agitation. The
measurement was repeated three times.
Results and discussion
Pellets of different composition, size and hardness
(Table 1) were chosen on purpose for this experiment to show the
influence of method variables on the friability of brittle and hard
pellets prepared by different techniques. Pellet friability was
tested in the same equipment (Roche Friabilator) under different
conditions (Table 2), but always with the equal amount of sample (10
g) and equal total number of revolutions (200). All the samples
exhibited similar residue moisture content (1.41–2.59%). Table 3
indicates hardness and friability of pellet samples.
It is obvious that with increasing pellet hardness
friability values of samples decrease despite of the friability test
conditions (Table 3). When tensile strengths of samples are compared
the lowest values, i.e. 0.26 MPa were noticed for pellet samples 1
and 2 with low hardness values. Equal tensile strength to break
pellets is probably given by the predominant properties of DHCl
either in pellets (sample 2: 55%) or in the active layer (sample
The highest tensile strength (1.19 MPa) was calculated for MCC
that are generally considered as very hard. Other tensile strength
values corresponded to the increasing pellet hardness and decreasing
pellet friability. Pellets prepared using the drug layering technique
generally showed higher sensitivity to friability conditions than
pellets produced by a rotoagglomeration (samples 1 and 3, Table 3,
and Figure 2). Furthermore when the inactive cores are compared,
better mechanical properties were obtained for active pellets with
LM/MCC cores than pellets started with only MCC cores (pellet
hardness of 2.84 vs. 0.87 N, calculated tensile strength of 0.45 MPa
vs. 0.26 MPa, and friabilities 0.29–1.91% vs. 0.50–3.16%). This
can be explained by different cores solubility and wettability. While
MCC cores are insoluble in water, which was used as wetting agent for
the layering, LM/ MCC cores were partly soluble due to high lactose
content (65%). For successful drug solution layering process it is
necessary to wet properly the solid surface of the starter. Only
under these conditions, droplets of the drug solution could spread
all over the solid surface and create a continuous drug layer. As LM/
MCC cores are partly soluble in water, one might presume their
surface is better wetted by the drug solution making the layering
process more effective and the drug layer adhering more tightly to
the core surface. The consequence indicates higher pellet hardness
and lower pellet friability. This theory was supported by SEM images
of layered pellets (Figure 3) and also photos of pellets after the
friability test (Figure 2). The left part of Figure 3 (sample 1)
shows clearly defined drug layer on MCC starter surface while on the
right side of this picture (sample 3) drug layer and starter surface
are not well distinguishable. On Figure 2a, the core surface without
active layer is clearly visible (sample 1) indicating thus that drug
layer is not binding tightly to the starter’s core. This feature is
less obvious on Figure 2b (sample 3) signalizing better active layer
to core sticking. On the other hand the surface of a sample prepared
by rotoagglomeration (Figure 2c) remains almost untouched after
agitation under comparable conditions showing thus high resistence
against a friction.
Pellets obtained by an agglomeration process in a
Rotoprocessor containing lower drug amount (sample 5) or drug free
pellets (sample 6) showed the highest hardness values (3.61 N and
4.89 N) and the lowest friability (0.14–0.26% and 0.07–0.18%,
respectively). These values were comparable to those obtained for
sample 4, i.e. commercially produced starters Celphere®
considered as mechanically highly resistant.
Since limit values for pellet friability were published
in the literature, i.e. less than 1.7% 22),
it is necessary to pay attention to the method used and its
parameters. As shown in our experiment, different friability values
of one sample can be obtained indicating either satisfactory or
unsatisfactory friability values. Especially brittle pellets are very
sensitive to the variables of friability method used.
This experimental work has been
supported by IGA VFU Project No 136/2008/FaF and the pharmaceutical
company Zentiva a.s. Praha, Czech Republic.
Received 4 November 2008 /
Accepted 1 December 2008
PharmDr. Miloslava Rabišková, CSc.
technologie léků FaF VFU
1–3, 612 42 Brno
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