European Journal of Pharmaceutical Sciences 135 (2019) 68–76

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European Journal of Pharmaceutical Sciences

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

The influence of core tablets rheology on the mechanical properties of press- T

coated tablets
⁎
Samantha Ascania,1, Alberto Berardib, Lorina Bisharatc, Giulia Bonacucinaa, Marco Cespia, ,
Giovanni Filippo Palmieria
a
School of Pharmacy, University of Camerino, Via Gentile III da Varano, Camerino, MC, Italy
b
Department of Pharmaceutical Sciences and Pharmaceutics, Faculty of Pharmacy, Applied Science Private University, Amman 11931, Jordan
c
Department of Pharmaceutics and Pharmaceutical Technology, School of Pharmacy, The University of Jordan, Amman 11942, Jordan

A R T I C LE I N FO A B S T R A C T

Keywords: Press-coating (also called compression coating or dry coating) consists of a second compression of an outer layer
Dry coating of material over a preformed tablet core. Despite being old, this technology has returned to popularity due to its
Press-coating widespread use in preparation of chronotherapeutic dosage forms. The literature available on press-coated ta-
Viscoelasticity blets has mainly investigated drug release kinetics, while there is a lack of information about their mechanical
Dynamic mechanical analysis
properties. Here we study, for the first time, the effect of material properties and manufacturing parameters on
Tensile strength
the mechanical characteristics of press-coated tablets. Firstly, we show that the stiffness of the bare core tablets
Porosity
depends on the material type and, in case of viscoelastic materials, also depends on the compression pressure.
We then demonstrate that less stiff (i.e. more viscoelastic) core tablets deform to a greater extent upon the
second compression and thus allow the formation of less porous, harder coats and with a more homogenous
density distribution. Finally, we find that changes in the mechanical properties of press-coated tablets over one
month storage are almost negligible. Our data suggest that viscoelastic rather than stiff cores should be used in
dry coating, as they promote the formation of more homogenous coats and with better mechanical properties.

1. Introduction or swell in aqueous environments. Following administration, the drug is

quickly released after a predetermined lag time based on the features of
Press-coating, also known as compression coating or dry coating, is the outer layer. Currently, several chronotherapeutic delivery platforms
a solvent-free coating technology where the coating material is com- make use of press-coating, such as Geoclock® (Skyepharma Production
pressed around a core tablet. Despite the fact that this technique has Sas), SyncroDose™ (Penwest Pharmaceuticals), Contramid CR (Labo-
been known since the end of the 19th century (Noyes, 1896) and that pharm Inc.) and OSDrC® OptiDose™ (Catalent Pharma Solutions).
the first production-scale machines were available since the fifties Several studies have been carried out on compression coating and
(Cole, 1995), press-coating technology has never really established it- the topic has been reviewed by Bose and Bogner (2007), and, more
self, remaining for long a niche process for the production of coated recently, by Lin and Kawashima (2012) and by Foppoli et al. (2017).
tablets (Cole, 1995). In the last 15 years, there has been a growing in- Most of the literature has focused on the evaluation of the influence of
terest in the use of dry coating for the production of pulsatile drug various factors on the kinetics of drug release in view of the use of dry
delivery systems which release drug at predetermined times and sites coated tablets as chronotherapeutic and colon targeting drug delivery
following oral administration (Bose and Bogner, 2007; Foppoli et al., systems. A relevant aspect that has been largely overlooked is the de-
2017; Lin and Kawashima, 2012), as for example chronotherapeutic termination of factors that could affect the mechanical properties of
and colon targeting drug delivery systems. Due to the wide use of press- press-coated tablets. Such an understanding is of foremost importance
coating for the manufacturing of chronotherapeutics, some authors in this technology, considering that the mechanical properties and the
classified it as “chronopharmaceutical technology” (Lin and integrity of final tablets can be compromised by inefficient bonding
Kawashima, 2012). For this application, an immediate-release core ta- between core and coat and by the expansion of core during the de-
blet is coated with a layer of polymeric material that can dissolve, erode compression and post-ejection phase (Cole, 1995; Windheuser and

⁎
Corresponding author at: School of Pharmacy, University of Camerino, Via Gentile III da Varano, 62032 Camerino, MC, Italy.
E-mail address: marco.cespi@unicam.it (M. Cespi).
1
Present affiliation: Technical Research & Development, Novartis Pharma AG, Basel, Switzerland.

https://doi.org/10.1016/j.ejps.2019.05.011
Received 31 January 2019; Received in revised form 3 May 2019; Accepted 17 May 2019
Available online 18 May 2019
0928-0987/ © 2019 Elsevier B.V. All rights reserved.
S. Ascani, et al. European Journal of Pharmaceutical Sciences 135 (2019) 68–76

Cooper, 1956). The effect of compaction pressure on the inner core (Lin For each blend and applied pressure, the analysis was performed in
et al., 2001) or the outer layer (Fukui et al., 2001a, 2001b; Lin et al., triplicate. Material tabletability and compressibility were determined
2001; Turkoglu and Ugurlu, 2002) was evaluated by several authors but by plotting the tensile strength and porosity of tablets, respectively, as a
only in terms of its influence on drug release or lag time. In addition, function of the applied pressure.
the potential effect of compression behaviour and mechanical proper-
ties of various materials used in inner cores on quality of press-coated 2.3. Preparation of inner core tablets
tablets was only suggested (Lin and Kawashima, 2012) and no data are
currently available. Here, we study, for the first time, the factors that Core tablets of 80 mg and a diameter of 6 mm were prepared by
could affect the mechanical properties of dry coated tablet. direct compression using the same blends in Section 2.2. For each
For the preparation of the inner cores, four materials with different material, tablets of different porosities were prepared according to their
compaction behaviour were selected: microcrystalline cellulose (MCC) specific tabletability and compressibility profiles. Specifically, inner
and hypromellose (HPMC) were chosen as model of soft, plastic mate- cores of MCC with 50, 25 and 15% porosity, and inner cores of HPMC
rials, α Lactose monohydrate (LAC) as model of moderately hard, brittle with 33, 25 and 15% porosity were prepared. PDC tablets with porosity
material and dicalcium phosphate dihydrate (PDC) as model of hard, of 25% and LAC tablets of 15% porosity could be only prepared.
brittle material (Roopwani and Buckner, 2011). Inner cores of different
porosities were prepared and analysed in terms of mechanical re- 2.4. Characterisation of inner core tablets
sistance and rheological behaviour using dynamic mechanical analysis.
The inner cores were also used to prepare press-coated tablets at dif- The inner core tablets were characterised for weight, thickness,
ferent compaction pressures, using HPMC in the outer layer. The me- breaking force, tensile strength and porosity. Furthermore, the core
chanical properties and the final porosity of both layers of the tablets tablets were analysed by dynamic mechanical analysis (DMA 8000,
were measured. These studies allowed the determination of the influ- Perkin-Elmer, USA). The cores were subjected to a frequency sweep test
ence of formulation parameters of the inner core (i.e. tensile strength, using a compression geometry to evaluate their rheological behaviour.
porosity and viscoelastic behaviour) on the properties of the outer layer A sinusoidal deformation of 2 μm was applied to the tablets over a
(i.e. tensile strength and porosity). The effect of the type of inner core range of frequencies from 1 to 10 Hz at ambient temperature. The strain
on the adhesion of layers was also studied. Finally, changes of me- amplitude and the linear viscoelastic region were determined by pre-
chanical properties of the dry-coated tablets were evaluated over one liminary strain sweep tests performed at 1 Hz in the deformation range
month storage at ambient conditions. of 1 to 10 μm. The results were recorded as the storage modulus (E'), the
loss modulus (E″) and the tan δ (E″/E′) as a function of the frequency.
2. Materials and methods For each condition (i.e. type of core material and %porosity), tests were
performed in triplicate.
2.1. Materials
2.5. Preparation of press-coated tablets
Hypromellose 2208 (HPMC) (METHOCEL K4M Premium CR EP,
Colorcon, Germany), microcrystalline cellulose (MCC) (Avicel PH-102, A mixture of 98.7% HPMC, 0.3 ferric oxide and 1% MgSt was used
FMC BioPolymer, Belgium), dicalcium phosphate dehydrate (PDC) to make the outer shell (i.e. powder coating layer). Ferric oxide was
(Emcompress, JRS Pharma, United States), α-lactose monohydrate used to colour the outer layer in order to easily distinguish the core
(LAC) (Pharmatose 100M, DMV Fonterra Excipients, Germany), ferric from the coat after the tablet breakage.
oxide (J.T.Baker, Netherland) and magnesium stearate (MgSt) (Acef, About 60% of the quantity of the outer layer coating material (equal
Fiorenzuola D'Arda, Italy) were all used as received. to 140 mg) was first filled into a 10 mm die, then the inner core tablet
was manually placed in the centre of the coating materials. The re-
2.2. Powder characterisation maining quantity (i.e. 100 mg) of the coating material was then poured
into the die and compressed into tablets. The press-coated tablets were
Blends of HPMC, MCC, PDC and LAC with 1% of magnesium stea- prepared at three different compression pressures, namely 45, 90 and
rate were prepared using a V-shape mixer (Laboratori Mag Divisione 180 MPa at a production rate of 10 rpm. The nominal weight of each
Artha, Italy). For each blend, 80 mg samples were compressed using a press-coated tablet was 320 mg, made of 80 mg inner core tablets and
10 station rotary tablet press (Riva Piccola, Ronchi, Italy) equipped 240 mg outer shell.
with 6 mm round, flat-faced punches and operating at a rotation speed
of 10 rpm. The punches penetration was set to generate different 2.6. Characterisation of press-coated tablets
compression pressures in the range between 30 and 250 MPa. Tablet
weight, breaking force (hardness tester, Erweka TBH 30, Germany), The press-coated tablets were characterised for weight, thickness
diameter and thickness (micrometer 103–137, Mitutoyo, Japan) were and breaking force. For press-coated tablets, tensile strength was not
measured. The tensile strength (σt) and porosity (ϕt) were then calcu- calculated due the anomalous breaking pattern observed during the
lated according to the following equations: hardness test (as reported in Section 3.3), which would render the
calculated tensile strength without physical meaning. Moreover, the
2H inner cores were retrieved after the press-coating and evaluated in
σt =
πDt (1) terms of weight, thickness, diameter and porosity. Weight and volume
where H is the breaking force, D is the diameter and t is the thickness of of the outer layers were also calculated as the difference between
the tablet. weight and volume of the press-coated tablets and the retrieved cores,
in order to determine the porosity of the outer layer. All the reported
⎛ ρbulk, t ⎞ results are the mean of three independent measures.
ϕt = ⎜1 − ∙100
ρreal, p ⎟ (2)
⎝ ⎠
2.7. Stability of press-coated tablets
where ρbulk,t is bulk density of the tablet calculated as the ratio between
the weight and volume, and ρreal,p is the density of the powder blend Selected batches of press-coated tablets were stored for one month
determined using helium pycnometer (AccuPic1330, Micromeritics, at ambient conditions. During this period, the tablets were monitored
USA). for weight, thickness, breaking force, and friability. The friability was

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measured using a USP friability apparatus (Tecno Galenica, Italy) op- are shown in Fig. 1. The tabletability results (Fig. 1A) are in agreement
erating at a rotation speed of 25 rpm for 4 min. After weighing, 20 ta- with previously reported data (Gustafsson et al., 1999; Zhang et al.,
blets from each batch were rotated for 100 revolutions and re-weighed 2003), showing that MCC and HPMC generated harder tablets with
to determine the percentage of weight loss. respect to lactose and dicalcium phosphate. The last two materials were
Tensile strength and friability were measured in triplicate at each not able to produce tablets with a measurable breaking force (minimum
time point. recordable values ≈ 7 N) at compression pressures lower than
150–170 MPa. The compressibility results (Fig. 1B) illustrate the ability
2.8. Adhesion test of the different materials to produce tablets at a predetermined por-
osity. At high pressure values, MCC, HPMC and LAC showed the same
To measure the adhesion force between the layers, i.e. inner core behaviour, producing tablets with porosity of around 15% in-
and outer shell, double layer tablets were prepared using a 6 mm die. dependently of the applied pressure, whereas PDC compacts were of
The inner core tablet, prepared as described in Section 2.3, was first higher porosity (≈25%). At low pressure values, MCC produced tablets
placed in the die, then 80 mg of the outer layer material was poured and of higher porosity than HPMC. Overall, these results suggest that only
tablets were compressed. Double layer tablets were prepared at three tablets of MCC and HPMC can be prepared in a wide range of porosity,
different compression pressures, namely 45, 90 and 180 MPa at a pro- yet hard enough to withstand handling. It is important to highlight that
duction rate of 10 rpm. the calculated values of porosity could be slightly overestimated, due to
The adhesion force was measured using a tensile tester apparatus the use of the helium pycnometer density. Helium pycnometer is the
(Model 5543, Instron Ltd., USA) equipped with a load cell of 10 N and a most broadly used technique for the estimation of true density of
cylindrical probe of 10 mm diameter. A slightly modified procedure pharmaceutical materials. However, it has been demonstrated that, in
with respect to those reported in the literature for the determination of the case of MCC, the helium pycnometer method results in an over-
adhesion force on double layer tablets (axial or tensile method) (Chang estimation of the true density of around 4–14% (Sun, 2005). Con-
et al., 2017; Kottala et al., 2012) was applied. Briefly, a double layer sidering the helium pycnometer density of MCC measured in this work
tablet was attached to the lower cylindrical probe using a cyanoacrylate (i.e. 1.55 g/cm3) and the true density of 1.46 g/cm3 reported by Sun
adhesive and further glue was placed on the top surface of the tablet. (2005), it is possible that the values of porosity obtained here are
The upper probe was lowered at a rate of 1 mm/min until the contact overestimated of around 2–3%.
with the tablet and constant force of 5 N was applied for 5 min. The
upper arm was withdrawn at a speed of 1 mm/min until the break of the 3.2. Characterisation of inner core tablets
bilayer compact. Preliminary tests showed that this procedure ensured
the break of the bilayer tablet at the interface between the two layers. Based on results obtained in Section 3.1, inner core tablets of MCC
Adhesion force was considered as the maximum force recorded on the and HPMC were prepared at three different porosities. MCC core tablets
force–displacement plot. of low (15%), intermediate (25%) and high (50%) porosity, and inner
Tests were performed in triplicate. cores of HPMC with low (15%), intermediate (25%) and high (33%)
porosity were prepared. PDC tablets with intermediate porosity of 25%
3. Results and discussion and LAC tablets with low porosity of 15% could be only prepared. The
physical characteristics of inner core tablets are presented in Table 1.
3.1. Powder characterisation Since the inner cores had to be compressed for a second time during
the preparation of the press-coated tablets, their stiffness was tested
The tabletability and compressibility of MCC, HPMC, LAC and PDC using dynamic mechanical analysis (DMA). All samples showed the

Fig. 1. A) Tabletability and B) compressibility profiles of MCC, HPMC, PDC and LAC.

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Table 1
Properties of all the prepared inner cores.
Inner cores Pressure Weight Thickness Porosity Tensile strength
(MPa) (mg) (mm) (%) (MPa)

MCCIC50 32,3 ± 1,2 80,6 ± 0,9 3,62 ± 0,02 49,9 ± 0,7 0,5 ± 0,1
MCCIC25 100,7 ± 3,8 80,4 ± 0,8 2,49 ± 0,03 24,7 ± 1,2 3,6 ± 0,7
MCCIC15 197,5 ± 12,5 80,7 ± 1,1 2,20 ± 0,03 16,1 ± 1,0 5,9 ± 0,2
HPMCIC33 40,7 ± 1,9 80,6 ± 0,8 3,21 ± 0,03 32,9 ± 0,6 0,5 ± 0,0
HPMCIC25 62,2 ± 2,5 80,4 ± 0,6 2,87 ± 0,03 25,2 ± 0,9 1,2 ± 0,3
HPMCIC15 149,5 ± 13,5 80,1 ± 1,2 2,55 ± 0,03 15,9 ± 0,7 3,4 ± 0,5
PDCIC25 179,8 ± 19,9 81,2 ± 0,7 1,59 ± 0,01 25,4 ± 0,4 0,7 ± 0,1
LACIC15 171,1 ± 7,3 80,9 ± 0,7 2,15 ± 0,01 15,3 ± 0,3 0,5 ± 0,1

Fig. 2. Effect of material type and porosity of core tablets on storage modulus (E′) and on tangent of phase angle (tan δ) as measured by dynamic mechanical analysis.

typical behaviour of solid-like materials, with very low tan δ values and 2011) and the stiffness and viscoelasticity of tablets. Materials with
much higher storage moduli (E′) (Fig. 2). The different behaviour of the high tendency to deformation during tableting (e.g. MCC and HPMC)
inner cores can be analysed by observing the plot of E′ versus the fre- produce tablets with high viscoelasticity and low rigidity. Instead,
quency of the applied stress (Fig. 2A). The results of DMA were able to materials that deform less upon compression (e.g. PDC) yield stiffer
differentiate between three groups of materials: LAC, PDC and cellulose tablets.
derivatives. PDC cores had the highest E′ and consequently were the
stiffest compacts. Cellulose derivatives cores possessed the lowest
stiffness which was frequency dependent to a certain degree. LAC cores 3.3. Characterisation of press-coated tablets
had an intermediate behaviour. The results of DMA also show that the
rigidity of the MCC and HPMC compacts decreased as the porosity in- The inner cores were used for the production of press-coated tablets.
creased. Nevertheless, viscoelasticity and stiffness of tablets were more These were manufactured by compression of an outer layer of HPMC on
influenced by the material type than by the porosity of compacts. the inner core, at three different compaction pressures: 45, 90 and
The tan δ values (Fig. 2B) highlights that the cellulosic cores, par- 180 MPa. The effect of the applied pressure on the breaking force of the
ticularly those with higher porosity, have a greater tendency to dis- press-coated tablets containing the different cores is reported in the
sipate energy during the deformation, indicating a greater liquid-like Fig. 3A. Interestingly, the breaking force of press-coated tablets was
behaviour. The tan δ results, together with the frequency dependence of dependent on the viscoelastic properties of the inner cores. The lower
E′, suggest higher viscoelasticity and consequently time-dependency of was the stiffness of the core, the higher was the breaking force of the
MCC and HPMC cores compared to PDC and LAC cores. This result is in press-coated tablets. For example, at a compression pressure of 90 MPa,
agreement with the literature, where MCC has been reported to have a the press-coated tablets prepared with MCCIC50 (i.e. the core with the
higher time-dependency compared to PDC and LAC when analysed by lowest stiffness) had breaking force values which were almost double
Heckel plots (strain rate sensitivity index) (Katz and Buckner, 2013; (≈170 N) those of tablets prepared with the MCCIC15, HPMCIC15,
Rees and Rue, 1978), indentation creep (Katz and Buckner, 2013) and LACIC15 and PDCIC25 inner cores. Fig. 3B shows that the breaking force
microindentation rheology (Çelik and Aulton, 1996). of press-coated tablets was also related to the porosity of the outer
It can be concluded that there is a correspondence between the layer. Thus, it appears that the use of more viscoelastic inner cores
behaviour of materials during compaction (Roopwani and Buckner, promoted the densification (reduction of porosity) of the outer layer
during compaction. Less porous coats provided, in turn, higher

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Fig. 3. Effect of compaction pressure on A) breaking force and B) porosity of the outer layer of press-coated tablets prepared with different inner cores.

mechanical resistance (i.e. breaking force). observed for the core tablets before the second compression (Fig. 6A).
We then determined the deformation of inner cores in press-coated However, press-coated tablets showed a different breaking pattern,
tablets by studying changes of cores' thickness and diameter (Fig. 4 and with the presence of breaking lines or cracks in the band width area
Supplementary Fig. SF1) and porosity (Fig. 5) before and after the near the loading platen. This anomalous breaking pattern has been
second compression. All the cores underwent a further deformation named as “delamination” by Shang et al. (Shang et al., 2013). Press-
process during the second compression event, with an increase of the coated tablets broke either in delamination alone or both delamination
diameter and a reduction of the thickness (Figs. 4 and SF1). The extent and tensile mode, as shown in Fig. 6B and C. Again, the type of the
of this deformation depended on the applied pressure, and the stiffness inner core determined the failure mode. In fact, press-coated tablets
of the cores. MCCIC50 tablets showed a massive change in tablet with stiff inner cores exhibited the delamination failure pattern alone,
thickness with a reduction of around 50% at 180 MPa; while the re- while those prepared with the least stiff cores (i.e. MCCIC50, HPMCIC33,
duction in thickness of PDCIC25 was only around 19% at the same ap- MCCIC25 and HPMCIC25) showed both patterns of failure. The extent of
plied pressure. Interestingly, the change in the diameter of the inner applied pressure during the second compression did not have any in-
core was much less evident and was almost independent of the core fluence on the failure mode (data not shown). According to Shang et al.
type (Fig. SF1). The deformation of the cores can also be quantified by the anomalous breaking pattern can be caused by different factors: ta-
plotting the change of core porosity versus the applied pressure (Fig. 5). blets geometry, inhomogeneous density distribution and presence of
The cores with the lowest stiffness (i.e. MCCIC50 and HPMCIC33) showed inherent defects (Shang et al., 2013). Since the geometry is the same for
a huge reduction in the porosity upon the second compression and as all the tablets, i.e. all are flat faced, the most likely causes for the
the applied pressure is increased, a greater drop in porosity is obtained. anomalous failure mode are the inhomogeneous density distribution
More rigid inner cores (i.e. MCC and HPMC cores with low initial and the presence of defects in the outer layer. The images of press-
porosity) showed less significant drop in porosity as a function of ap- coated tablets (Fig. 7) seem to support this hypothesis: the top surface
plied pressure. Finally, the change in porosity was almost negligible for of press-coated tablets prepared with the less stiff cores appears
the stiffest core tablets (i.e. LACIC15 and PDCIC25). Putting these results homogeneous in colour. Instead, the tablets prepared with the stiffer
together with the previous ones, we can notice that upon the second core tablets present a darker circle in the centre of the top surface,
compression less stiff (i.e. more viscoelastic) cores deformed more possibly indicating a higher density area in the outer core, located in
(Figs. 4, 5 and SF1) and thus possibly absorbed more efficiently the correspondence to the inner core. In addition, the press-coated tablets
energy of compression, resulting in greater densification (i.e. lower prepared with the stiffer core tablets showed small cracks in the tablet
porosity) and strength of the outer core, as shown in Fig. 3A and B. waist. In agreement with the previous results shown in Fig. 3, the more
Another interesting aspect is represented by the way the tablets deformable viscoelastic cores promoted easier press-coating, and
break during the hardness test. Usually, tablets break in tensile mode, formed more homogenous coats and with less defects.
with a breaking line perpendicular to the direction of the load appli-
cation (Fell and Newton, 1970). This mode of failure was always

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Fig. 4. Images of inner core tablets made of MCC with 50% (MCCIC50) porosity and PDC with 25% porosity (PDCIC25) before and after the preparation of press-coated
tablets (i.e. 2nd compression).

3.4. Adhesion between layers although, the highest adhesion forces were recorded when tablets with
the lowest stiffness were used (i.e. MCCIC50, HPMCIC33), particularly at
The adhesion force between inner core and outer layer is another the highest compaction pressure of the outer layer. Comparing inner
relevant factor for successful preparation of press-coated tablets. To test cores of the same porosity, i.e. 15%, the highest adhesion with the outer
the effect of inner core feature on the layer adhesion, we used a pro- layer material was found with LAC and DCP. These results suggest that
cedure previously developed for bilayer tablets (Chang et al., 2017; the layer adhesion is a complex phenomenon that cannot be directly
Kottala et al., 2012). Readers should note that this procedure measures related with the mechanical properties of the inner core.
the force necessary to detach the core from the coating, pulling the coat
only axially and from the top surface. The measured values of the ad-
hesion force are reported in Fig. 8. A general trend cannot not be found,

Fig. 5. Effect of compaction pressure on the porosity of inner cores retrieved from press-coated tablets.

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Fig. 6. Failure modes of A) inner cores, B) press-coated tablets prepared with inner cores of low stiffness (in the figure HPMCIC33, 2nd compression at 45 MPa), C)
press-coated tablets prepared with inner cores of high stiffness (in the figure LACIC15, 2nd compression at 90 MPa).

Fig. 7. Images of press-coated tablets prepared with MCC inner core of 50% porosity (MCCIC50) and HPMC inner core of 15% porosity (HPMCIC15) at three different
compaction pressures.

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Fig. 8. Effect of pressure on the adhesion force between HPMC and materials of inner core.

different stiffness: MCCIC50, PDCIC25, and MCCIC15. The results are

shown in Fig. 9: the friability did not change over time, whereas the
breaking force was reduced. The reduction in breaking force was more
evident for the press-coated tablets prepared at high pressure using
MCC as inner core. This finding is probably related to the nature of MCC
itself: in fact, it is known that a greater elastic recovery after compac-
tion is expected for predominately plastic materials (as MCC) than for
fragmenting ones (as PDC) (Haware et al., 2010; YORK and BAILY,
1977). Greater elastic recovery of the core over storage is likely to
translate into lower mechanical resistance of the whole press-coated
tablet. Interestingly, the reduction in tablet breaking force was not
enough to affects friability. Overall, changes of these two mechanical
properties over storage were small and can be considered negligible for
all the formulations tested.

4. Conclusion

In press-coating, less stiff – more viscoelastic - cores deform more

and promote the formation of coats with less defects, more homogenous
density distribution and higher mechanical resistance. The effect of core
material can be explained by the greater tendency of the viscoelastic
cores to deform compared to the stiff ones upon the second compres-
sion. These findings reveal, for the first time, the significant impact of
the core tablet characteristics on the mechanical properties. Ultimately,
the mechanical properties of the tablets influence their quality. Thus, it
is now evident that the quality of press-coated tablets can be promoted
by selecting and manufacturing viscoelastic cores.
Supplementary data to this article can be found online at https://
Fig. 9. Effect of storage time on A) friability and B) breaking force of press- doi.org/10.1016/j.ejps.2019.05.011.
coated tablets prepared with three different inner cores, namely MCC of 50%
porosity (MCCIC50), MCC of 15% porosity (MCCIC15) and PDC of 25% porosity References
(PDCIC25) at 45 and 180 MPa compression pressures.
Bose, S., Bogner, R.H., 2007. Solventless pharmaceutical coating processes: a review.
3.5. Stability of the press-coated tablets Pharm. Dev. Technol. 12, 115–131. https://doi.org/10.1080/10837450701212479.
Çelik, M., Aulton, M.E., 1996. The viscoelastic deformation of some tableting materials as
assessed by indentation rheology. Drug Dev. Ind. Pharm. 22, 67–75. https://doi.org/
The variation of mechanical properties over time is a well-known 10.3109/03639049609043873.
issue in the manufacturing of press-coated tablets, due to the retarded Chang, S.-Y., Li, J., Sun, C.C., 2017. Tensile and shear methods for measuring strength of
bilayer tablets. Int. J. Pharm. 523, 121–126. https://doi.org/10.1016/j.ijpharm.
elastic expansion of the core tablets (Cole, 1995). Thus, we decided to 2017.03.010.
test both the breaking force and friability of the tablets over one month. Cole, G.C., 1995. Introduction and overview of pharmaceutical coating. In: Cole, G.C.
This time period is considered long enough to dissipate all the retarded (Ed.), Pharmaceutical Coating Technology. Taylor and Francis Ltd..
Fell, J.T., Newton, J.M., 1970. Determination of tablet strength by the diametral-com-
elastic energy (Haware et al., 2010; Picker, 2001; YORK and BAILY, pression test. J. Pharm. Sci. 59, 688–691. https://doi.org/10.1002/jps.2600590523.
1977). The analysis was carried out on press-coated tablets prepared at Foppoli, A., Maroni, A., Cerea, M., Zema, L., Gazzaniga, A., 2017. Dry coating of solid
high and low pressure values, using three types of core tablets of dosage forms: an overview of processes and applications. Drug Dev. Ind. Pharm. 43,
1919–1931. https://doi.org/10.1080/03639045.2017.1355923.

75
S. Ascani, et al. European Journal of Pharmaceutical Sciences 135 (2019) 68–76

Fukui, E., Miyamura, N., Kobayashi, M., 2001a. An in vitro investigation of the suitability prepared by direct compression with micronized ethylcellulose. J. Pharm. Sci. 90,
of press-coated tablets with hydroxypropylmethylcellulose acetate succinate 2005–2009. https://doi.org/10.1002/jps.1151.
(HPMCAS) and hydrophobic additives in the outer shell for colon targeting. J. Noyes, P.J., 1896. Apparatus for sugar coating pills. US Patent 568488.
Control. Release 70, 97–107. https://doi.org/10.1016/S0168-3659(00)00332-1. Picker, K.M., 2001. Time dependence of elastic recovery for characterization of tableting
Fukui, E., Miyamura, N., Kobayashi, M., 2001b. Effect of magnesium stearate or calcium materials. Pharm. Dev. Technol. 6, 61–70. https://doi.org/10.1081/PDT-100000014.
stearate as additives on dissolution profiles of diltiazem hydrochloride from press- Rees, J.E., Rue, P.J., 1978. Time-dependent deformation of some direct compression
coated tablets with hydroxypropylmethylcellulose acetate succinate in the outer excipients. J. Pharm. Pharmacol. 30, 601–607. https://doi.org/10.1111/j.2042-
shell. Int. J. Pharm. 216, 137–146. https://doi.org/10.1016/S0378-5173(01) 7158.1978.tb13340.x.
00580-4. Roopwani, R., Buckner, I.S., 2011. Understanding deformation mechanisms during
Gustafsson, C., Bonferoni, M.C., Caramella, C., Lennholm, H., Nyström, C., 1999. powder compaction using principal component analysis of compression data. Int. J.
Characterisation of particle properties and compaction behaviour of hydroxypropyl Pharm. 418, 227–234. https://doi.org/10.1016/j.ijpharm.2011.05.040.
methylcellulose with different degrees of methoxy/hydroxypropyl substitution. Eur. Shang, C., Sinka, I.C., Jayaraman, B., Pan, J., 2013. Break force and tensile strength re-
J. Pharm. Sci. 9, 171–184. https://doi.org/10.1016/S0928-0987(99)00054-8. lationships for curved faced tablets subject to diametrical compression. Int. J. Pharm.
Haware, R.V., Tho, I., Bauer-Brandl, A., 2010. Evaluation of a rapid approximation 442, 57–64. https://doi.org/10.1016/j.ijpharm.2012.09.005.
method for the elastic recovery of tablets. Powder Technol. 202, 71–77. https://doi. Sun, C., 2005. True density of microcrystalline cellulose. J. Pharm. Sci. 94, 2132–2134.
org/10.1016/j.powtec.2010.04.012. https://doi.org/10.1002/jps.20459.
Katz, J.M., Buckner, I.S., 2013. Characterization of strain rate sensitivity in pharmaceu- Turkoglu, M., Ugurlu, T., 2002. In vitro evaluation of pectin–HPMC compression coated
tical materials using indentation creep analysis. Int. J. Pharm. 442, 13–19. https:// 5-aminosalicylic acid tablets for colonic delivery. Eur. J. Pharm. Biopharm. 53,
doi.org/10.1016/j.ijpharm.2012.09.006. 65–73. https://doi.org/10.1016/S0939-6411(01)00225-9.
Kottala, N., Abebe, A., Sprockel, O., Bergum, J., Nikfar, F., Cuitiño, A.M., 2012. Windheuser, J., Cooper, J., 1956. The pharmaceutics of coating tablets by compression. J.
Evaluation of the performance characteristics of bilayer tablets: part I. Impact of Pharm. Sci. 45, 542–545. https://doi.org/10.1002/jps.3030450812.
material properties and process parameters on the strength of bilayer tablets. AAPS YORK, P., BAILY, E.D., 1977. Dimensional changes of compacts after compression. J.
PharmSciTech 13, 1236–1242. https://doi.org/10.1208/s12249-012-9845-9. Pharm. Pharmacol. 29, 70–74. https://doi.org/10.1111/j.2042-7158.1977.
Lin, S.Y., Kawashima, Y., 2012. Current status and approaches to developing press-coated tb11248.x.
chronodelivery drug systems. J. Control. Release 157, 331–353. https://doi.org/10. Zhang, Y., Law, Y., Chakrabarti, S., 2003. Physical properties and compact analysis of
1016/j.jconrel.2011.09.065. commonly used direct compression binders. AAPS PharmSciTech 4, 489–499.
Lin, K.-H., Lin, S.-Y., Li, M.-J., 2001. Compression forces and amount of outer coating https://doi.org/10.1208/pt040462.
layer affecting the time-controlled disintegration of the compression-coated tablets

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