Preparation of delayed-release multiparticulate formulations of diclofenac sodium and evaluation of their dissolution characteristics using biorelevant dissolution methods

Abstract

Diclofenac sodium was used as a model drug for preparation of delayed-release (DR) multiparticulates, which were further processed into solid oral dosage forms such as capsules and tablets. Multiple unit pellets systems (MUPS) were prepared from different types of starter pellets (inert cores) including microcrystalline cellulose pellets, sugar spheres, isomalt pellets and novel calcium phosphate-based pellets. The study results showed that the material of the inert cores affected both mechanical properties of the drug-loaded pellets and the dissolution characteristic of the model drug. Biorelevant dissolution method carried out with the help of a pHysio-grad device allowed thorough examination of the developed formulations in the environment mimicking pH conditions along gastrointestinal tract. This method revealed significant differences between the formulations and their sensitivity to variable hydrodynamic conditions.

Full text

Journal of Drug Delivery Science and Technology 60 (2020) 101986
Available online 18 August 2020
1773-2247/© 2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Research paper
Preparation of delayed-release multiparticulate formulations of diclofenac
sodium and evaluation of their dissolution characteristics using biorelevant
dissolution methods
Daniel Zakowiecki
a
,
*
, Maja Szczepanska
b
, Tobias Hess
a
, Krzysztof Cal
b
, Barbara Mikolaszek
b
,
Jadwiga Paszkowska
c
, Marcela Wiater
c
, Dagmara Hoc
c
, Grzegorz Garbacz
c
,
d
a
Chemische Fabrik Budenheim KG, Rheinstrasse 27, 55257, Budenheim, Germany
b
Department of Pharmaceutical Technology, Faculty of Pharmacy, Medical University of Gdansk, Al. Gen. J. Hallera 107, 80-416, Gdansk, Poland
c
Physiolution Polska Sp. Z o.o., Skarbowcow 81/7, 53-025, Wroclaw, Poland
d
Physiolution GmbH, Walther-Rathenau-Strasse 49a, 17489, Greifswald, Germany
ARTICLE INFO
Keywords:
Multiple unit pellets systems
Calcium phosphate-based pellets
Diclofenac sodium
Starter pellets
pHysio-grad
ABSTRACT
Diclofenac sodium was used as a model drug for preparation of delayed-release (DR) multiparticulates, which
were further processed into solid oral dosage forms such as capsules and tablets. Multiple unit pellets systems
(MUPS) were prepared from different types of starter pellets (inert cores) including microcrystalline cellulose
pellets, sugar spheres, isomalt pellets and novel calcium phosphate-based pellets. The study results showed that
the material of the inert cores affected both mechanical properties of the drug-loaded pellets and the dissolution
characteristic of the model drug. Biorelevant dissolution method carried out with the help of a pHysio-grad
device allowed thorough examination of the developed formulations in the environment mimicking pH condi-
tions along gastrointestinal tract. This method revealed signicant differences between the formulations and
their sensitivity to variable hydrodynamic conditions.
1. Introduction
Multiparticulate drug delivery systems (MDDS) are novel pharma-
ceutical dosage forms, which have been gaining increasing popularity in
recent years when compared to single unit dosage forms. These multiple
unit dosage forms (MUDF) are made of numerous independent subunits
(microparticles), where each of them is an autonomous reservoir of a
drug and releases the drug in a desirable way, independently of the other
subunits. Multiparticulates are especially suitable for preparation of
modied-release solid oral dosage forms (delayed- or sustained-release),
which offer such benets as less variable gastrointestinal transit or
reduced risk of dose dumping. At the present time, the most commonly
used multiparticulates are coated pellets which are formulated into oral
dosage forms either by lling them into hard gelatin capsules or com-
pacting into tablets (Multiple Unit Pellet System, MUPS) [1–4].
One of the well-established ways of preparation of multiparticulates
is drug layering of spherical starter pellets (also called inert cores or
beads) followed by coating these drug-loaded pellets with a thin
polymer-based lm. Drug layering of inert cores offers relatively easier
technology compared to extrusion and spheronisation process. More-
over, it enables the production of multiparticulates with a very uniform
particle size distribution as well as advantageous surface morphology [5,
6]. There is a wide range of various types of neutral starter pellets
commercially available on pharmaceutical market offering different
characteristics [7,8]. Sugar spheres (nonpareils), which were introduced
on the market and applied for the production of multiparticulates as
rst, are still the most popular. Sugar spheres are made of sucrose
(usually up to 92%) and corn starch [9]. They are soluble in aqueous
media and hygroscopic, which is often a challenge during coating [10].
Absorbed water can be problematic and impact stability of moisture
sensitive drugs [8]. That is why alternative products have been intro-
duced to the market and interest in their use is constantly growing. The
most commonly employed substitutes are cellulose pellets consisting of
100% microcrystalline cellulose (MCC). They are insoluble in water and
are characterized by high sphericity as well as good mechanical
strength. Due to these properties, the drug layering can be carried out
faster and with reduced formation of undesirable agglomerates, which
shortens the coating time and reduces cost of production. However,
* Corresponding author.
E-mail address: daniel.zakowiecki@budenheim.com (D. Zakowiecki).
Contents lists available at ScienceDirect
Journal of Drug Delivery Science and Technology
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https://doi.org/10.1016/j.jddst.2020.101986
Received 2 April 2020; Received in revised form 31 July 2020; Accepted 31 July 2020

Journal of Drug Delivery Science and Technology 60 (2020) 101986
2
problems such as the absorption of certain drugs on the surface of cel-
lulose bers or swelling in contact with water, which can affect disso-
lution pattern have been reported [11–13]. Another solution available
on the market are starter pellets consisted of polyalcohols such as iso-
malt, mannitol, xylitol. Similarly to sugar spheres, they are hygroscopic
and soluble in aqueous media, however, they are promoted due to their
low glycemic index and lack of cariogenic effect [5,14]. Within this
group, isomalt pellets offer especially interesting functionality of
creating internal osmotic pressure, which modulates dissolution pattern
of some drugs [15]. Recently, a new type of water-insoluble pellets
based on anhydrous dibasic calcium phosphate (DCPA) has been intro-
duced to the market. These pellets consist of 80% w/w of DCPA and 20%
w/w of MCC. Due to their elevated density of above 1000 g/l, very low
water content of less than 1%, and reduced hygroscopicity, they repre-
sent an attractive alternative to the other commercial products offered
so far. A detailed comparison of various functional properties of calcium
phosphate-based pellets with other commercially available inert cores
can be found elsewhere [16].
Inert cores are made of excipients commonly used in the pharma-
ceutical industry, which are neutral and should not exhibit any phar-
macological activity nor interact with the drug substance in a way,
which may adversely affect its stability and/or effectiveness. Never-
theless, characteristics of starter pellets may have a signicant impact on
the course of the production process as well as can inuence the rate of
drug dissolution not less than the properties of coating polymer. Thus,
the drug release pattern can be determined by the thickness of the
coating and its permeability, but also by the geometry of the pellets,
surface morphology or the osmotic pressure originating from the pellets
cores [5,8,15,17–20].
As has been already mentioned, drug-loaded pellets can be lled into
hard gelatin capsule shells or compressed into tablets. Especially, the
latter technology of tabletting of microparticulates is very interesting
and allows combining the advantages of both tablets and pellets-lled
capsules in one dosage unit [21–23]. In this case, the properties of
pellet cores together with the coating polymer will determine the
durability of the drug-loaded pellets and protect them from damages
during tabletting. It has been frequently reported that the size of pellets
is a very important factor to be considered during compaction. Nor-
mally, small pellets are employed in preparation of tablets as they are
less affected by the compression process. This is mainly due to the higher
mechanical strength of smaller beads relative to their size as well as
reduced contact force on each individual pellet resulting in signicantly
reduced degree of transformation [24,25].
In this work the suitability of different types of starter pellets in the
development of delayed-release multiparticulate formulations contain-
ing diclofenac sodium as a model drug was evaluated. Diclofenac so-
dium is a nonsteroidal anti-inammatory drug (NSAID) having both
analgesic and antipyretic activities. The drug is commonly used in the
treatment of rheumatic disorders. Diclofenac sodium is available in a
number of preparations of 25 mg, 50 mg or 75 mg strength [26–28]. The
drug is a weak acid of BCS Class II and shows pH-dependent solubility in
physiological pH range which increases with the increase of pH value
[29,30]. Diclofenac sodium is often formulated as enteric-coated prep-
aration to avoid direct contact of the drug with the mucosa resulting in
local gastrointestinal toxicity. For this purpose pH-sensitive enteric
polymers are commonly used. These polymers should limit the release of
the drug in acidic conditions of stomach and allow rapid dissolution of
the drug in duodenum and distal parts of the gastrointestinal tract (GIT)
[31].
The development of drug products is a time-consuming process and
involves high costs. Thorough examination of drug formulations with
the help of reliable in vitro biorelevant techniques facilitates screening
of the candidates and makes this process more efcient. Biorelevant
dissolution methodologies allowing an adequate prediction of the in
vivo performance of drugs come here with help [32,33]. In the present
work a novel device, pHysio-grad, which enables biorelevant simulation
of the intestinal pH was employed [34]. The pHysio-grad can precisely
monitor and adjust the pH value of hydrogen carbonate buffer, which is
considered to be one of the most biorelevant medium for simulation of
intestinal conditions [35,36]. The carbonate buffer is a complex system
and its pH is an effect of dynamic interplay between all its constituents.
The thermodynamic instability leads to spontaneous increase of pH due
to the loss of carbon dioxide (CO
2
). This effect might be minimized by
either preventing CO
2
evaporation (by using appropriate sealing or
covering a dissolution medium with an organic layer) or by compen-
sating the loss of CO
2
with the help of an automated system. Moreover,
carbonate buffers give the opportunity for simulation of dynamic
intraluminal pH changes, however, continuous and dynamic adjustment
of pH value must be provided in order to use them in routine dissolution
testing.
The main objective of this work was to investigate the suitability of
different types of starter pellets in the development of delayed-release
multiparticulate formulations containing diclofenac sodium as a model
drug. The planned scope of research included the use of commercial
inert cores made of microcrystalline cellulose, sugar, isomalt as well as
novel calcium phosphate-based pellets in preparation of both hard
gelatin capsules and compressed tablets. The additional objective was to
examine and compare the effect of the core material on the in vitro drug
release of the model drug using compendial as well as biorelevant
dissolution methods.
2. Materials and methods
Diclofenac sodium (Amoli Organics, Mumbai, India). Film coating
systems: Vivacoat® FM-1M 000 (JRS Pharma, Rosenberg, Germany) and
Aquarius® Control ENA (Ashland, Covington, KY, USA). Inert cores:
calcium phosphate-based (DCPA) pellets - PharSQ® Spheres CM M
(Chemische Fabric Budenheim, Budenheim, Germany), microcrystalline
cellulose pellets - VIVAPUR® MCC Spheres 500 (JRS Pharma, Rosen-
berg, Germany), sugar spheres - pharm-a-spheres™ MESH 35-25 (Hanns
G. Werner GmbH, Tornesch, Germany), isomalt starter pellets - gale-
nIQ™ 960 (BENEO-Palatinit GmbH, Mannheim, Germany). Microcrys-
talline cellulose VIVAPUR® 200 (JRS Pharma, Rosenberg, Germany).
Low-substituted hydroxypropyl cellulose (L-HPC) LH-11 (ShinEtsu,
Wiesbaden, Germany). Magnesium stearate (Peter Greven Fett-Chemi,
Venlo, The Netherlands). Transparent hard gelatin capsule shells, size
“0” (Kapselwelt, Hude, Germany).
2.1. Preparation of drug-loaded DR pellets
The starter pellets used in this study were initially calibrated be-
tween two sieves, 500
μ
m and 710
μ
m, in order to obtain grains of
similar dimensions and to avoid the effect of different particle sizes on
the coating process as well as on analyses results. Sieved pellets were
drug-layered with diclofenac sodium in a ProCepT 4M8-Trix Fluid-bed
system (FBS) equipped with a Wurster column (ProCepT nv, Zelzate,
Belgium). Around 100 g of starter pellets were rst coated with a
aqueous suspension containing 5% w/w of the drug substance and 5%
w/w of Vivacoat® system up to about 20% of weight gain. Subsequently,
without breaking the process, the pellets were sprayed with puried
water (intermediate coating) and nally coated with 20% w/w aqueous
suspension of Aquarius® Control ENA (enteric-coating) until around
10% of weight gain was reached. The use of an intermediate coating step
allowed maintaining the continuity of the entire process and adjusting
the process parameters before the following coating phase. Moreover, it
reduced interactions between the two layers and the accumulation of
static charges. During all phases the machine settings were maintained
at the following values: air speed of around 0.21 m
3
/min, inlet air
temperature of around 63 ◦C, product temperature of around 40 ◦C,
nozzle pressure of 1 bar.
D. Zakowiecki et al.

Journal of Drug Delivery Science and Technology 60 (2020) 101986
3
2.2. Preparation of multiparticulate dosage forms
Enteric-coated pellets containing the model drug were used to
formulate two types of solid oral dosage form - hard gelatin capsules and
compressed tablets. Developed MUPS formulations consisted of around:
50.0% w/w of the diclofenac sodium pellets (equivalent to 25 mg of
diclofenac sodium), 44.5% w/w of MCC type 200, 5.0% w/w of L-HPC
and 0.5% w/w of magnesium stearate. Hard gelatin capsules were pre-
pared by manual lling of the diclofenac sodium pellets into capsule
shells of “0” size. Tablets were compressed on a Korsch EK0 eccentric
tablet press (Korsch, Berlin, Germany) using concave punches (R 25
mm) of 12 mm diameter under a compaction forces of 18–20 kN.
2.3. Scanning electron microscopy
To visualize surface properties of the drug-loaded DR pellets alone,
as well as compressed into tablets, a scanning electron microscope
Phenom Pro (Phenom World Thermo Fisher, Eindhoven, Netherlands)
was employed. Standard sample holder and a carbon tape were used to
x a sample and acceleration voltage of 5–10 kV was applied to record
images at a magnication of 300x.
2.4. Mechanical strength
The mechanical strength of starter pellets as well as drug-loaded DR
pellets was assessed with a texture analyzer equipped with a 6 mm
diameter cylindrical stainless steel probe in compression mode (TA.XT
Plus, Godalming, Surrey, England). The probe was moved vertically
downwards at a speed of 2.0 mm/s until the triggering force of 0.1 N was
detected and further with a speed of 0.05 mm/s until a pellet was
crushed. The maximum force at the point of fracture and the distance to
break were recorded. All measurements (for each type of sphere n =12)
were performed at room temperature.
2.5. Dissolution test (modied compendial method)
According to The United States Pharmacopeia monograph for
diclofenac sodium delayed-release tablets, dissolution test is carried out
in two steps, between which test samples must be transferred from the
one medium to the other. In the case of enteric-coated tablets a paddle
apparatus is applicable because the transfer of such tablets is not a major
problem. However, in the case of microparticulates the use of a basket
apparatus is more convenient. In this study both hard gelatin capsules
and tablets containing enteric-coated diclofenac sodium pellets were
placed in a basket apparatus (USP apparatus 1) PTWS 820D (Phar-
maTest AG, Hainburg, Germany) and the dissolution test was carried out
according to the monograph for Diclofenac Sodium Delayed-Release
Tablets given in USP42/NF37 using a rotational speed of 100 rpm.
During the rst phase the capsules were incubated in 0.1 M hydrochloric
acid for 2 h. In acidic stage, according to both USP/NF and Ph.Eur.
gastro-resistant pellets should not release more than 10% of labeled
content of a drug. In the subsequent buffer stage, release of the drug
should be rapid and reach minimum 80% of the labeled amount of
diclofenac sodium within 45 min. The amount of the dissolved drug was
determined using a T70 UV/VIS Split-Beam Spectrophotometer (Phar-
maTest AG, Hainburg, Germany) at the detection wavelength of 276 nm
using ow-through quartz cuvettes with 1 cm path length.
2.6. Biorelevant dissolution in hydrogen carbonate buffer using a pHysio-
grad device
The pHysio-grad device used in this study was composed of a
microcomputer, which controlled independently each measurement
channel and a valve island. pH probes assured constant pH measurement
in each vessel and triggered adjustment of pH when necessary. The
adjustment of pH values was obtained by addition of a titrant, which was
CO
2
and compressed air in this case (Fig. 1).
Dissolution was carried out in a paddle apparatus (USP apparatus 2)
at a 50 rpm paddle rotational speed. Dissolution test was composed of
two stages. In the rst stage tablets or pellets (taken out from capsule
shells) were placed in a vessel lled with 250 mL of 0.01 M HCl for 30
min. After this time 750 mL of Hank’s buffer concentrate was added and
the test continued for 60 min. After addition of buffer, the pH of
hydrogen carbonate medium was controlled by pHysio-grad device and
set at 6.8. The amount of the dissolved drug was determined using an
Agilent 8453 UV/VIS Spectrophotometer (Agilent Inc. Santa Clara, CA,
USA) at the detection wavelength of 276 nm using quartz cuvettes with
1 cm path length.
3. Results
3.1. Mechanical strength
Mechanical strength of starter pellets and drug-loaded DR pellets was
assessed with a texture analyzer. The maximum force at the point of
fracture (hardness) and the distance to break vs. pellets breaking
strength [N] are shown in Figs. 2 and 3. The highest value of hardness
was recorded for MCC spheres, and the lowest for sugar-based inert
cores. Generally, it was observed that for all types of starter pellets the
coating process signicantly improved the mechanical strength of the
particles. The increase in robustness was the most pronounced in case of
water-insoluble pellets (MCC and DCPA). It can be noted that for iso-
malt-, sugar- and MCC-based pellets values of the standard deviation are
relatively high which could result from their not quite spherical shape.
Drug-loaded enteric-coated pellets based on isomalt and sugar exhibited
very similar response to the compression. They deformed relatively fast
when exposed to external force until reaching the point of fracture as
shown in Fig. 3. Deformation of DCPA-based pellets was signicantly
slower. It can be noted that the maximum force at the breaking point is
at similar level as for isomalt pellets, but the distance to reach fracture
point was signicantly extended. This can be the effect of the specic
composition of DCPA-based inert cores, which combine the features of
brittle calcium hydrogen phosphate and a ductile material (microcrys-
talline cellulose).
3.2. Scanning electron microscopy
Surface structure and cross-sections of the drug-loaded DR pellets
before and after compression into tablets were studied with a scanning
electron microscope. Fig. 4 shows SEM micrographs of drug-loaded
diclofenac sodium pellets before compression (left column), com-
pressed pellets inside tablets (middle column) and pellets extracted from
the surface of tablets (right column). SEM images of cross-sections show
Fig. 1. Schematic diagram of the pHysio-grad device.
D. Zakowiecki et al.

Journal of Drug Delivery Science and Technology 60 (2020) 101986
4
that the shape of sugar- and DCPA-based drug-loaded pellets is spher-
ical, whilst isomalt and MCC show more ellipse-like character. In all
cases a clear distinction between a core and a coating layer can be
spotted with no visible deformation of the coating layer. The coating
layer is uniform through the whole cross-sections with layer thickness of
approximately 30
μ
m. Although the irregular shape of the some types of
examined inert cores could have caused a variation in the coating
thickness, no such observations were made. It can be seen that even after
compression the original shape of the pellets located inside the tablets
generally remained unchanged, without visible deformations or dam-
ages of the coating layer. However, it should be noted here that many
pellets positioned on the very surface of the tablets, which were in direct
contact with the punches during compaction, displayed cracks in the
polymer layer and partial shape deformation. The most pronounced
cracks are visible for pellets made of sugar, isomalt and MCC. Especially
sugar-based pellets were heavily deformed, which led to partial expo-
sure of their cores.
3.3. Dissolution test (modied compendial method)
Four types of commercially available inert cores (DCPA pellets, MCC
spheres, sugar spheres and isomalt pellets) were used to prepare
delayed-release multiparticulate formulations (hard gelatin capsules
and tablets) of diclofenac sodium at a dose of 25 mg. All of them were
analyzed using modied compendial methods for diclofenac sodium
delayed-release tablets (USP42/NF37). Comparison of the amount of the
drug released in the acidic medium is given in Fig. 5. During this phase
both hard gelatin capsules and tablets disintegrated completely and
Fig. 2. Comparison of breaking strength (hardness) of inert cores made of DCPA, MCC, sugar and isomalt with corresponding drug-loaded DR pellets (given are
means of min. 10 repetitions, SD is indicated by the error bars).
Fig. 3. The distance to break and the maximum force at the point of fracture of drug-loaded enteric-coated pellets based on DCPA, MCC, sugar and isomalt (given are
examples of single deformation proles).
D. Zakowiecki et al.

Journal of Drug Delivery Science and Technology 60 (2020) 101986
5
water-insoluble ingredients formed a cone at the bottom of dissolution
vessels. In the baskets remained practically only pellets with very small
residue of excipients. It was observed that the water-soluble inert cores
(made of sugar and isomalt) tended to oat in the upper part of baskets,
whereas the insoluble ones (DCPA and MCC) remained mostly at the
bottom of baskets. All examined formulations demonstrated their
gastro-resistance and released much less than 10% of the labeled
amount of diclofenac sodium within 2 h of the test. However, in case of
preparations containing water-soluble starter pellets higher dissolution
of the drug substance can be detected. It can also be noticed that tablets
containing inert cores with MCC, sugar and isomalt released less amount
of the drug than analogous capsules. The opposite situation occurred in
case of phosphate pellets, where the release of diclofenac sodium from
tablets is slightly higher than from capsules.
Fig. 4. SEM micrographs of drug-loaded diclofenac sodium DR pellets (magnication of 300x).
Fig. 5. The release of diclofenac sodium from gastro-resistant diclofenac sodium preparations in acid phase (after 2 h incubation in 0.1 M HCl) (given are mans of n
=6, SD is indicated by the error bars).
D. Zakowiecki et al.

Journal of Drug Delivery Science and Technology 60 (2020) 101986
6
In the buffer stage all tested formulations demonstrated rapid
dissolution and released the whole amount of the drug within required
45 min (Fig. 6). It can be noted that multiparticulates containing water-
soluble substances showed identical, measurably faster dissolution rate
in comparison to insoluble MCC and DCPA cores. In the case of phos-
phate pellets, the release of diclofenac sodium from tablets is slightly
slower than from hard gelatin capsules, while in the other examined
formulations these differences are not so visible. After completing this
phase in the baskets containing DCPA and MCC microparticulates still
the whole quite spherical cores could be observed while for water-
soluble sugar and isomalt beads the baskets were practically empty. In
the case of MCC spheres, a large amount of retained red dye (which is a
component of the enteric-coating) can be seen. (Fig. 7).
3.4. Biorelevant dissolution in hydrogen carbonate buffer using a pHysio-
grad device
Biorelevant dissolution test has shown the high discriminatory
power and revealed signicant differences between the tested formu-
lations in terms of the impact of the dosage form as well as the core
material on the dissolution rate. Moreover, the use of a paddle apparatus
enabled visual observation of the tested samples directly in dissolution
vessels.
The results presented in Fig. 8 show that drug-loaded pellets con-
taining sugar and isomalt, both alone (without capsule shells) and
compressed into tablets, released diclofenac sodium faster than corre-
sponding MCC and DPCA cores. In addition, the release of the model
drug from these tablets and free pellets was virtually identical and the
dosage form had no effect on its dissolution rate. These ndings are in
line with the results obtained in the dissolution test based on the com-
pendial method (Fig. 6). A different situation can be observed in the case
of pellets containing water-insoluble MCC and DCPA. Here, the differ-
ences between the two dosage forms are clearly visible. The dissolution
rate from pellets is much slower than from corresponding tablets. This
difference is noticeably larger in the case of DCPA cores.
Examination of free pellets allowed observation of their different
dissolution behavior which might be related to the core material. Sugar-
and isomalt-based pellets were mobile and tended to oat in the entire
volume of dissolution medium. Dosing of a gaseous titrants in the second
stage of the test additionally stimulated the movement of pellets in the
vessel which could promote dissolution of diclofenac sodium. On the
contrary, MCC- and DCPA-based pellets exhibited more stationary
behavior. Especially pellets containing DCPA, due to their elevated
density, were lying still at the bottom of the vessels even during addition
of gaseous titrants. The limited movement resulted in much lower
dissolution rate, particularly in comparison with sugar and isomalt
cores. DCPA-based pellets did not release the whole of the labeled
amount of diclofenac sodium within 60 min of the test. Additional
intensive mixing was needed to release all the substance (results not
included in the diagram).
Signicant differences in dissolution pattern between tablets and
free pellets could be observed, especially at the very beginning of the
second stage of the dissolution test. First samples were withdrawn in 1
min after addition of Hank’s buffer (Fig. 9). All tested tablets have
released more than 20% of label amount of diclofenac sodium within
this time, which could be caused by the presence of excipients that
promoted movement of freed pellets and increased their exposure to the
dissolution medium. For comparison, at the same time the free pellets
released a much smaller amount of the drug substance (about 12–13%
for sugar and isomalt pellets, 11% for MCC cores and only 4% for DCPA
cores). In case of pellets based on water-insoluble material, contrary to
tablet formulations, free pellets showed less tendency to move and were
lying at the bottom of the dissolution vessels. It could be also observed
that dosing of the gaseous titrant had a greater effect on movement of
isomalt and sugar cores and facilitated their oating in the entire volume
of the dissolution medium.
4. Discussion
The aim of this work was to compare the suitability of different types
of starter pellets in the development of delayed-release multiparticulate
formulations containing the model drug - diclofenac sodium. Four types
of commercial inert cores of pharmaceutical grade were selected for the
research. Two of them were soluble in aqueous media – sugar spheres
and isomalt pellets. Other two, microcrystalline cellulose spheres and
calcium phosphate-based pellets, were insoluble in water. Starter pellets
available on the market differ signicantly in size which can signi-
cantly impact properties of multiparticulate formulations including their
dissolution characteristics [37–39]. In order to eliminate impact of
particle diameters on results of analyses the cores used in this study were
normalized and only the 500–710
μ
m fraction was utilized. A chemical
nature of the core material determined not only the solubility but also
Fig. 6. Dissolution rate of diclofenac sodium from various multiparticulates in the buffer stage (given are mans of n =6, SD is indicated by the error bars).
D. Zakowiecki et al.

Journal of Drug Delivery Science and Technology 60 (2020) 101986
7
the functional properties of starter pellets that were inuencing the
process of drug layering of the cores. For instance, different tendencies
to accumulate electrostatic charges have been observed. Fig. 10 shows
pictures of FBS chamber taken about 5 min after the start of the process.
In case of MCC, sugar and isomalt cores, high adherence of the particles
to the glass walls of the granulator, caused by static electricity, is clearly
visible. Fluidization of DCPA beads is smooth and undisturbed. More-
over, in the case of water-soluble inert cores, especially made of isomalt,
initial extensive formation of dust has been noticed. This observation
corresponds to the data published earlier and showing higher friability
of these inert cores [16].
Starter pellets differed in terms of hardness expressed here as
breaking strength (see Fig. 2) The most durable were MCC spheres, the
lowest mechanical strength was observed for sugar- and DCPA-based
inert cores. The coating of inert cores – in this case with a water sus-
pension of hydroxypropyl methylcellulose (HPMC) mixed with the equal
amount of diclofenac sodium – signicantly improved mechanical
strength of the pellets. The greatest improvement was observed for
DCPA pellets for which hardness value increased by over 2.25 times. In
the course of research, no clear relationship between pellets hardness
and resistance to crush during tabletting could be observed. Considering
that the coating thickness for all pellets was identical (around 30
μ
m),
the differences in their robustness had to be due to the properties of the
core material. Drug-loaded enteric-coated sugar spheres with the lowest
value of breaking strength were affected the most during compression
(see Fig. 4). Nevertheless, when comparing coated pellets of similar
hardness, i.e. based on isomalt and DCPA, one can notice much less
compression damages of these latter. This difference is probably due to
Fig. 7. Residues of diclofenac sodium DR pellets (DCPA, MCC, sugar, isomalt) at the bottom of basket after completing the buffer stage.
Fig. 8. Dissolution rate of diclofenac sodium from various multiparticulates in the hydrogen carbonate buffer pH 6.8 (biorelevant test condition) (given are mans of
n =3 SD is indicated by the error bars).
D. Zakowiecki et al.

Journal of Drug Delivery Science and Technology 60 (2020) 101986
8
the longer time needed to reach the fracture point for the phosphate-
based pellets, as shown in Fig. 3. Furthermore, the inert cores made of
ductile MCC with the highest value of breaking strength were damaged
even more than previous two types. It should be mentioned here that the
pellets of the sizes used in this study (500–710
μ
m) are normally not
employed for preparation of MUPS tablet. However, a similar approach
has been successfully applied for research purposes and reported by
Hiew et al. [40] In this case, however, such particle dimensions allowed
precise observation of the coating layer and its deformation or damages
arose during compression into tablets. It is also important that the
damages were limited to the pellets located on the very surface of the
tablets, which had direct contact with steel parts of tableting tooling. It
can therefore be assumed that many of the observed cracks were caused
mechanically and the use of larger amounts of cushioning excipients
could signicantly reduce the damages.
Diclofenac sodium is known to cause adverse GI side effect after oral
administration [29]. Thus its preparations are commonly enteric-coated
in order to reduce gastric exposure. Enteric-coating should limit release
of the active substance in the stomach as much as possible and then
allow quick dissolution in the duodenum and distal GIT. In the present
studies, the quality of the coating layer has been evaluated after pro-
longed storage under acidic conditions, reecting those prevailing in the
stomach, as it is recommended in Ph.Eur. (chapter 2.9.3.) or USP/NF
(chapter 711). After 2 h of maceration in 0.1 M HCl, it was found that all
tested microparticulates met the compendial requirements and did not
release more than 10% of the labeled content of the active substance (see
Fig. 5) proving their gastro-resistance. It can be noted, however, that the
drug-loaded pellets based on water-insoluble cores released less diclo-
fenac sodium than water-soluble ones. When comparing MUPS tablets
and capsules, one can also observe slight differences in the amount of the
drug substance dissolved. For tablets containing sugar, isomalt or MCC
cores, the release of diclofenac sodium under acidic conditions was
lower than from corresponding capsules. The smallest change was
observed in the case of microparticulates based on MCC. This observa-
tion is unexpected as the analysis of SEM micrographs (see Fig. 4)
revealed damages to the polymer layer of many pellets after compres-
sion. Probably during prolonged maceration in aqueous solution of hy-
drochloric acid, the polymer coating was hydrated and formed hydrogel
Fig. 9. The release of diclofenac sodium after 30 min incubation in 0.01 M HCl and 1 min after addition of hydrogen carbonate buffer (given are mans of n =3 SD is
indicated by the error bars).
Fig. 10. Chamber of uid bed system after around 5 min of the coating process containing 1) DCPA pellets, 2) MCC spheres, 3) sugar spheres, 4) isomalt pellet.
D. Zakowiecki et al.

Journal of Drug Delivery Science and Technology 60 (2020) 101986
9
which sealed microparticulates interior. Interestingly, however, this
phenomenon has a larger magnitude in the case of pellets compressed
into tablets which might result from the very close contact of
drug-loaded pellets surface with excipients caused by compaction
forces. DCPA-based DR pellets behaved differently and after compres-
sion into tablets released more active substance. This could be explained
by a less effective sealing of the enteric-coating during maceration. It
should be noted that the difference between tablets and capsules
formulation was not big and the amount of dissolved diclofenac sodium
in this case was at the same level as for MCC cores and furthermore,
much lower than for both sugar- and isomalt-based multiparticulates.
The assumption about the sealing of the coating layer is to a certain
degree justiable, taking into account the results shown in Fig. 9 where
four times shorter maceration in much smaller volume of diluted acid
did not cause such sealing effect and allowed much higher release of
active substance from tablets when compared to the corresponding free
pellets (taken out from capsule shells). The highest difference was
observed for DCPA-based microparticulates, nevertheless, it should be
noted that the release of diclofenac sodium from the tablets containing
calcium phosphate cores is lower that from other tested MUPS tablets.
For formulation containing MCC- and isomalt-based DR pellets, big error
values can be spotted. In the rst case, this may be due to the plastic
nature of the cores and their signicant deformation during compression
resulting in a different coating thickness. For isomalt-based drug-loaded
pellets this phenomenon is related to the high solubility of the core
material in water. From the very beginning of the dissolution test, both
uncompressed and compressed multiparticulates were partly oating on
the surface of the dissolution medium, where parts of the pellets were
not immersed in the medium.
Comparing results of the dissolution carried out in buffers of neutral
pH using modied compendial method in a basket apparatus (see Fig. 6)
and the biorelevant method in a paddle apparatus (see Fig. 8), a very
similar relationship between the drug release rate and the chemical
nature of inert cores was found: dissolution rate from water-soluble
sugar- and isomalt-based multiparticulates was much faster than from
insoluble ones. Furthermore, in the case of drug-loaded pellets based on
water-soluble inert cores the release of diclofenac sodium from both
tablets and hard gelatin capsules was insensitive to differences in hy-
drodynamic conditions generated in a paddle or a basket apparatus,
showing similarly fast dissolution rate, normally exceeding 85% of the
amount of the drug substance within rst 15 min of the test. The
dissolution rate from tablets containing MCC- and DCPA-based multi-
particulates was slightly slower and their release proles had a similar
shape. In the case of uncompressed DR pellets lled in capsules, a very
high susceptibility of the drug release to the hydrodynamic conditions in
an apparatus was found. Comparing the results obtained using the
basket and paddle methods, one can observe much slower dissolution
rate for the latter method. This is due to the fact that the water-insoluble
pellets cores, especially DCPA-based ones, had a higher density and
tended to lay on the bottom of dissolution vessel directly under the
paddles, where mixing intensity is normally the lowest. Interestingly
though, under these conditions the release prole observed for calcium
phosphate pellets was very close to 0-order kinetics.
5. Conclusions
In the course of this study, delayed-release multiparticulate formu-
lations of diclofenac sodium in the form of tablets and hard gelatin
capsules were developed. As a basis for the preparation of the multi-
particulates, the starter pellets containing sucrose, isomalt, microcrys-
talline cellulose and anhydrous dibasic calcium phosphate were used. It
has been shown that the core material signicantly inuenced the
coating process, the properties of drug-loaded pellets as well as their
dissolution behavior. For diclofenac sodium, it seems more advanta-
geous to use starter pellets based on water-insoluble substances such as
MCC or DCPA, which showed the lowest degree of the drug release in the
acid phase. This may result in lower concentration of diclofenac sodium
in the gastric lumen and reduce stomach irritation.
The tableting of drug-loaded enteric-coated pellets revealed slightly
different resistance to compression and susceptibility to mechanical
damages of investigated inner cores. It can be assumed, the use of starter
pellets of smaller size would result in obtaining more rugged multi-
particulates, more suitable for formulation into tablets as reported
elsewhere [37,39,41].
The dissolution rate of diclofenac sodium from developed formula-
tions in neutral conditions mimicking these in the distal GIT was clearly
related to the solubility of the core material in water – very rapid for
soluble cores made of isomalt and sugar, slower for insoluble ones (MCC-
and DCPA-based).
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