bài báo nói về công nghệ bào chế hiện đại trong viên nén chứa pellet chúng ta sẽ thấy cái nhìn tổng quan cùng những vấn đề được rút kết từ nhiều nghiên cứu khác về dạng thuốc pellet và viên nén chứa pellet phóng thích theo nhịp.
Trang 1Shajahan Abdul, Anil V Chandewar, Sunil B Jaiswal ⁎
P Wadhwani College of Pharmacy, Yavatmal, Maharashtra, 445001, India
a b s t r a c t
a r t i c l e i n f o
Article history:
Received 30 November 2009
Accepted 12 May 2010
Available online 19 May 2010
Keywords:
Pellets
Compaction of pellets
Tableting of pellets
Multiple-unit pellet system
MUPS
Oral modified-release multiple-unit dosage forms have always been more effective therapeutic alternative to conventional or immediate release single-unit dosage forms With regards to thefinal dosage form, the multiparticulates are usually formulated into single-unit dosage forms such asfilling them into hard gelatin capsules or compressing them into tablets There are many relevant articles and literature available on the preparation of pellets and coating technology However, only few research articles discuss the issue of compaction of pellets into tablets This review provides an update on this research area and discusses the phenomena and mechanisms involved during compaction of multiparticulate system and material and/or process-related parameters influencing tableting of multiparticulates to produce multiple-unit pellet system (MUPS) or pellet-containing tablets, which are expected to disintegrate rapidly into individual pellets and provide drug release profile similar to that obtained from uncoated pellets
© 2010 Elsevier B.V All rights reserved
Contents
1 Introduction 2
2 Tableting of uncoated pellets 4
2.1 Compaction of microcrystalline cellulose pellets 4
2.2 Compaction of microcrystalline cellulose pellets containing other excipients 5
2.3 Effect of nature of granulationfluid 7
2.4 Effect of drying methods 7
3 Tableting of coated pellets 8
3.1 Nature and amount of polymers 8
3.1.1 Cellulosic polymers 8
3.1.2 Acrylic polymers 9
3.2 Effect of plasticizers 10
3.3 Effect of pellet size 10
3.4 Pellet core 11
3.5 Tableting excipients 11
3.5.1 Nature and Amount of Excipients 11
3.5.2 Particle size of excipients 13
3.5.3 Homogeneity and divisibility of tableted pellets dosage form 14
4 Conclusions 14
References 14
1 Introduction
Modified-release dosage forms (MRDF) have always been more
effective therapeutic alternative to conventional or immediate-release
dosage forms The objective of MRDF for oral administration is to control the release of the therapeutic agent and thus control drug absorption from gastrointestinal tract Such a dosage form effectively reduces adverse-effects associated with peak plasma concentration beyond that needed for therapeutic effectiveness while maintaining the plasma level above or at that needed to achieve therapeutic effect for a longer period The dosage form, in effect, controls the amount of drug available for absorption from one dose administration to the next resulting in a more
⁎ Corresponding author Tel.: +91 7232245847; fax: +91 7232238747.
E-mail address: sbjaiswal@yahoo.com (S.B Jaiswal).
0168-3659/$ – see front matter © 2010 Elsevier B.V All rights reserved.
Contents lists available atScienceDirect
Journal of Controlled Release
j o u r n a l h o m e p a g e : w w w e l s ev i e r c o m / l o c a t e / j c o n re l
Trang 2stable plasma level profile By reducing the side-effect profile of drug
entities and allowing for less frequent dosing regimens, these dosage
forms may improve the overall cost-effectiveness of drug therapy
Therefore, MRDF for new chemical entities are being considered on a
routine basis than ever before Within the context of this article, the
term modified-release refers to both delayed- and extended- or
prolonged-release system for oral administration
Modified-release preparations can be administered orally in single
or multiple-unit dosage forms Single-unit formulations contain the
active ingredient within the single tablet or capsule, whereas
multiple-unit dosage forms comprise of number of discrete particles
that are combined into one dosage unit They may exist as pellets,
granules, sugar seeds (non-pareil), minitablets, ion-exchange resin
particles, powders, and crystals, with drugs being entrapped in or
layered around cores[1–3] Although, similar drug release profiles can
be obtained with both the dosage forms, multiple-unit dosage forms
offer several advantages over single-unit systems such as
non-disintegrating tablets or capsules[4] When multiple-unit systems
are taken orally, the subunits of multiple-unit preparations distribute
readily over a large surface area in the gastrointestinal tract and these
small particles (b2 mm) behave like liquids leaving the stomach
within a short period of time Their small size also enables them to be
well distributed along the gastrointestinal tract that could improve
the bioavailability, which potentially could result in a reduction in
local drug concentration, risk of toxicity, and side-effects[2]
Inter-and intra-individual variations in bioavailability caused by, for
example food effects, are reduced [1,5] Premature drug release
from enteric-coated dosage forms in the stomach, potentially
resulting in degradation of drug or irritation of gastric mucosa, can
be reduced with coated pellets because of more rapid transit time
when compared to enteric-coated tablets[1,5] In the multiple-unit
system, the total drug is divided into many units Failure of few units
may not be as consequential as failure of a single-unit system This is
apparent in sustained-release single-unit dosage form, where a failure
may lead to dose-dumping of the drug[1] Other advantages of this
divided dose include ease of adjustment of the strength of a dosage
unit, administration of incompatible drugs in a single dosage unit by
separating them in different multiparticulates and combination of
multiparticulates with different drug-release rates to obtain the
desired overall release profile
With regards to thefinal dosage form, multiparticulates can be
filled into hard gelatin capsules or be compressed into tablets of which
the former is more common Unfortunately, the production costs for
capsules are high and their production rate is low compared with
those of tablets This is due to the lower output of capsulefilling
machines and to the higher cost of capsules themselves Although it is
recognized that oral administration of multiple-unit dosage form is
preferred over single-unit system, it is not advisable to present a
low-potency, highly dosed drug as a multiparticulate drug delivery system,
mainly because of poor patient compliance due to large capsule size
[6] Moreover, capsules cannot be divided into subunits in the same
way as tablets These disadvantages make compression of subunits
into rapidly disintegrating tablets an interesting issue The advantages
of tableting of multiparticulates include a reduced risk of tampering
(e.g Tylenol®and Sudafed-12)[7], and lower tendency of adhesion of
dosage form to esophagus during swallowing[8] Tablets from pellets
can be prepared at low cost when compared to pellet-filled capsules
because of the higher production rate of tablet process The expensive
control of capsule integrity afterfilling is also eliminated In addition,
tablets containing multiparticulates can be scored without losing
modified-release properties thus allowing a more flexible dosage
regimen Tableting of pellets as opposed to that of powder also results
in reduction of dust [9] It may also provide an opportunity to
understand the compaction process by examining the change in size,
shape and density of pellets after their compaction and retrieval of
individual pellets from disintegration tubes[6]or from the highly
lubricated compacts, which provides a reduction in the coherence of the pellets[10]
Compaction of pellets is a challenging area Only a few multiple-unit containing tablet products are available, such as Beloc®ZOK[11], Antra® MUPS [12] and Prevacid® SoluTabTM [13] Compaction of multiparticulates into tablets could either result in a disintegrating tablet providing a multiparticulate system during gastrointestinal transit or intact tablets due to the fusion of the multiparticulates in a larger compact.Fig 1illustrates two different types of MUPS: one comprising of coated pellets (reservoir systems), and the other prepared by compaction of matrix and/or uncoated drug pellets Ideally, the compacted pellets should not fuse into a non-disintegrat-ing matrix durnon-disintegrat-ing compaction and should disintegrate rapidly into individual pellets in gastrointestinalfluids to attain more uniform concentration of active substances in the body Importantly, the drug release should not be affected by the compaction process The challenges of formulating pellets into tablets are evident With reservoir-type coated-pellet dosage forms, the polymeric coating must be able to withstand the compaction force It may deform but should not rupture, since, for example, the existence of crack in the coating may have undesirable effects on the drug release properties of that subunit The type and amount of coating agent, the size of subunits, selection of external additives, and the rate and magnitude
of pressure applied must be considered carefully to maintain the desired drug release properties of that subunit[7].Fig 2is aflow chart representing factors influencing design of MUPS tablets To avoid problems arising from compaction of pellets, formulation scientist must have a comprehensive knowledge of how the pellets behave during tableting as well as how the material and/or process-related parameters affect the performance of that formulation as a drug delivery system This article reviews the phenomena and mechanisms involved during compaction of particulate system, key variables affecting compaction, and materials and/or process-related para-meters influencing performance of tableted multiparticulates
Fig 1 Schematic representation of types of MUPS — (a) MUPS comprising of coated
Trang 32 Tableting of uncoated pellets
It is the purpose of this section to discuss the compaction behavior
of uncoated pellets, prepared by extrusion and spheronisation
technology, and to study whether it can be controlled The effect of
process variables on beads will not be discussed in this section It is
suggested thatfive mechanisms are involved in the compression of
irregular granules— repositioning, deformation (a change in shape of
individual granules), densification (a reduction in granule porosity),
fragmentation (fracturing of granules into small aggregates) and
attrition of small aggregates (primary particles are sheared-off from
the granules during compression Owing to the irregular shape and
surface roughness of the granules, it is rather difficult to determine the
degree of incidence of the suggested mechanisms Recently, the use of
nearly spherical units (hereafter referred to as pellets) brought new
light into the mechanistic knowledge of the compaction process of
such units and justified the use of these units as an alternative model
system[10,14–18]
The mechanistic conception proposed[10]regarding the
compac-tion process of pellets can be summarized in a four stage model
(Fig 3), as follows: 1) volume reduction of the pellets by
rearrange-ment of pellets tofill inter-particle voids 2) volume reduction of pellet
bed by local surface deformation involving surfaceflattening of pellets
3) bulk deformation of pellets (change in pellet dimensions) in
parallel with densification of pellets and 4) cessation of the volume
reduction owing to low inter- and intra-granular porosity During the
first two stages in this sequence, there is an marked degree of volume
reduction but the strength of compressed bed is very low i.e the
inter-granular bonding force is not sufficiently strong to cohere the pellets
into a compact The bulk deformation of pellets (stage III) results in stronger inter-granular bonding, which is further increased during stage IV, even though the volume reduction in this stage is minute From this model, it was concluded that the relevant compression mechanisms involved in the compression of pellets are permanent deformation and incident of pellet fragmentation and attrition is low
or non-existent The terms pellet deformation and fragmentation used here refers to structural changes of pellets as such, and not to primary particles of which the pellets are formed, i.e., the shape of the pellet changes (deformation) or the pellets breakdown to smaller units (fragmentation)
2.1 Compaction of microcrystalline cellulose pellets The compression and compaction behavior of pellets formed from microcrystalline cellulose (MCC) has been investigated by Johansson
et al [10,14] They indicated that during compaction, MCC pellets compressed by deformation and the incidence of pellet fragmentation was low or non-existent Another important report of this study was that the porosity of the MCC pellets controlled both the degree of deformation and densification SEM revealed that low porosity pellets undergo limited permanent deformation during compression and the pellet porosity remains unaffected by the compression But the high porosity pellets undergo both a high compression-induced change in shape and a marked decrease in pellet porosity However, these data were obtained for pellets of similar original size The studies on the compactability of granules have informed that, the size of the aggregates could affect their compactability The authors[15]further prepared MCC pellets of size fractions 425 to 500 µm and 1250–
1400 µm, having similar porosity of 38% and compacted them in order
to investigate the effect of pellet size on the compression mechanism
of MCC pellets The studies showed that the original size of the pellets did not affect the volume or porosity changes of the tablet with moderate tablet formation pressure that led to the degree of densification of pellets and were independent of the original size However, the degree of deformation of pellets during compression (at
160 Mpa) was higher for larger pellets which may be possibly explained in following ways:firstly, it seems reasonable that larger pellets probably have a wider distribution in porosity and pore size within the pellets which gives rise to a higher deformability of the pellet if deformation occurs byflow of primary particles within the pellets Secondly, the pores between the pellets are probably larger for the larger pellets and larger space might allow a higher degree of deformation This might explain a reduced degree of deformation at very low inter-granular tablet porosities but also, the more limited degree of deformation for smaller pellets Finally, during uniaxial compression of an assembly of particles, it is normally assumed that the force applied to the powder is transmitted through the powder bed at points of interparticulate contact Increasing the size of the particles will reduce the number of force transmission points Thus, the contact force at each interparticulate contact point will increase, which might lead to increased pellet deformation The authors suggested that the structure of the inter-granular pore system was similar between tablets prepared from differently sized pellets and the inter-granular porosity of the tablet was very low at the highest applied pressure At these low porosities, the inter-granular pore system might have been closed for tablets prepared from the larger pellets, corresponding to large areas of contacts between pellets At such low tablet porosities, even a very limited increase in pellet deformation resulted in a marked increase in tablet strength[10] There are few other studies in the literature which have specifically reported a relationship between size of the aggregates and their compactability The most frequently reported effect of granule size seems to be that the reduction in size corresponds with an increase in tablet strength[19–21] However, Bangudu et al.[22]reported that the tablet strength was independent of granule size and the same
Fig 2 Flow chart representing factors influencing compaction of reservoir pellets.
Fig 3 Schematic compaction mechanism of pellets under the compression force The
degree of compression of pellets (represented by curved line) and the tensile strength
of tablets prepared from pellets (sloping dotted line) as a function of applied pressure.
Trang 4finding was reported by Rehula [23] for granules of size 0.26 to
1.5 mm In the latter study, the strength of tablets did increase when
granules N1.5 mm were compacted Adams and McKeown [24]
derived an agglomerate strength from compaction data and suggested
that this strength was independent of pellet size
2.2 Compaction of microcrystalline cellulose pellets containing other
excipients
Addition of other excipients to MCC can modify the tableting
characteristics of pellets Schwartz et al studied the compaction
behavior of uncoated beads made from MCC, lactose and DCP[25]
MCC is classified as a plastic material [26], lactose consolidates
primarily by fragmentation and then by plastic deformation [27]
while DCP compacts primarily by fragmentation[26] Among these
excipients, MCC could form beads by itself Neither lactose nor DCP
alone could form beads This might be due to the lack of sufficient
plasticity needed for spheronisation Beads were formed after the
addition of 22.5% of MCC into each one of these materials SEM
showed that MCC beads were not compressible (soft tablets) and very
few bonds were formed between beads Lactose/MCC beads were
more compressible and exhibited more fracture than the MCC beads
(hard tablets) DCP/MCC beads were more compressible than the
other two formulations (hardest tablets) The authors concluded that
DCP/MCC beads, at very low pressure (100 MPa), undergo plasticflow
more easily than lactose/MCC (400 MPa) and MCC (550 MPa) beads
In another study of Johansson et al.[16,17], the tableting behavior of
pellets prepared from a 4:1 mixture of DCP and MCC was studied and
compared with the compaction behavior of pellets made solely from
MCC SEM photograph of DCP/MCC pellets revealed that there was
limited bulk deformation and extensive deformation at the pellet
surface The authors suggested that when the primary particles
become harder, it would be more difficult for them to flow within the
pellet and the pellet would thus be more rigid and less prone to
deform and densify during compression However, the more rigid
nature of the pellets leads to change in mode of deformation during
compaction The strength of tablets formed from MCC pellets was
more markedly dependent on the porosity of the pellets than that of
tablets formed from DCP/MCC pellets At higher pellet porosities,
tablets formed from MCC pellets were stronger than those formed
from DCP/MCC pellets, while at lower pellet porosities, the tablet
tensile strength was similar to both types of pellet which may be due
to the difference in the mode of pellet deformation as mentioned
above (bulk deformation vs surface deformation)
The effect of waxy material, glyceryl behenate on the deformation
behavior and compression characteristics of MCC alone and in
combination with acetaminophen (APAP) beads was investigated
[28] The relationship between densification and pressure during
compression was compared for these formulations at one maximum
upper punch stroke with Heckel plots The densification plot showed
transition in the extent of plastic deformation, elastic deformation,
and fracture of the bead formulation at different maximum punch
strokes In the absence of wax in the formulation, a higher pressure
was required to deform (or fracture) the MCC beads When APAP
(10%) was added to this formulation, there was a dramatic decrease in
tablet strength and it required even greater pressure to produce intact
compacts The drop in tablet strength might be due to the disruption
of bond formation between MCC particles by APAP, a poorly
compressible material itself Hence, even at high pressure (and
possible fracturing), APAP/MCC bead formulation produced weak
tablets This study showed that formulations containing less than 10%
wax had less consolidation or higher yield pressures and exhibited
more elastic recovery upon ejection than those with 30% or more wax
The study indicated that an increase in the wax level in the beads
increases plasticity of the formulation which makes densification by
plastic deformation the probable dominant deformation mechanism
The result of this study was also confirmed by York and Pilpel[29] They studied the relationship between a mixture of lactose and four fatty acid powders and their tableting, and concluded that waxes, like fatty acids, are typical plastic materials that exhibit type C powder characteristics of Heckel plot They show steep linear slopes, indicating little or no evidence of particle rearrangement and densification is by plastic deformation and possible asperity melting They also reported that mixture of fatty acids with lactose powder shows a change in consolidation behavior from type B (consolidation
by particle fragmentation) to type C (consolidation by plastic deformation) as the level of fatly acids in the mixture is increased
In another study, the effect of incorporating a soft material (polyethylene glycol; PEG) into pellets of MCC on the compression behavior and compactability of the pellets were investigated[30] The tableting properties of these pellets (prepared from a 1:1 (w/w) mixture of PEG 6000 and MCC) were compared with those of two types of MCC pellets: one of relatively low pellet porosity, similar to that of the MCC/PEG 6000 pellets, and one with substantially higher porosity The degree of compression of the pellets and the porosity, permeability to air and tensile strength of the resulting tablets were determined Some of the tablets were also deaggragated, and the thickness and porosity of the retrieved pellets were determined The pellets formed from the MCC/PEG mixture were more compressible and the degree of compression levelled off at a lower pressure than both types of MCC pellets The study of inter-granular porosity and tablet permeability with applied pressure showed that MCC/PEG pellets were more comparable to the high porosity MCC pellets with respect to their deformation behavior than to the MCC pellets of equal original porosity At the highest pressure, virtually all inter-granular void space had disappeared from the tablets formed from MCC/PEG pellets It was concluded that the incorporation of soft material increased the deformation propensity of the pellets during tableting
It has been suggested[10,14]that the differences in compactability between different pellet types are related to the ability of the pellets
to form areas of inter-granular contact at which bonding between pellets can occur which in turn is controlled by degree of permanent deformation which the pellets undergo during compression Maganti and Celik[31]observed significant changes between the compaction properties of powder and pellets formed from the same formulation They studied the compaction behavior of uncoated pellets prepared from MCC alone or in combination with 10% propranolol hydrochloride and either 10% lactose or 10% DCP The tensile strength of compacts prepared from powders was significantly higher than the tensile strength of compacts prepared from pellets The major mechanism of compression of powders appeared to be plastic deformation whereas their pellets exhibited elastic deforma-tion and brittle fragmentadeforma-tion which resulted in compacts of lower tensile strength This study was also confirmed by Wang et al[32] Compacts prepared from lactose/MCC beads had different compac-tion/consolidation behavior than powders of the same composition The tensile strength of compacts prepared from powders increased with increase in MCC content, while compacts prepared from pellets showed the opposite trend This could be for reason that the degree of bonding of MCC had been affected by the changes in shape and size, possibly by loss of plasticity of MCC during granulation process, and reduction in the number of binding sites due to pelletization process The compaction and compression of diclofenac sodium (10% w/w) matrix pellets made from xanthan gum (XG, 16% w/w) and one of the three different fillers: lactose monohydrate (LAC), tribasic calcium phosphate (TCP) and β-cyclodextrin (β-CD), at 16% w/w) were investigated [33] In their further study [34], two pellet formu-lations were studied which contained MCC (50% w/w), model drug (10% w/w), xanthan gum as the contact release agent (16% w/w); LAC (16% w/w) and povidone as the binder (8% w/w) to investigate the
influence of physicochemical properties of model drug on the compaction of the respective matrix pellets SEM of all types of
Trang 5matrix pellets in both the studies showed a compression-induced
change in shape and marked pellet deformation (i.e pelletsflattened)
occurred in the direction of the applied stress during compression
This implied that volume reduction of these units could have been an
important change induced during compression Such a behavior was
in agreement with observations earlier reported [14–18] Matrix
pellets comprising TCP had higher increase, raising its density after
compression by approximately 15% of their original apparent density,
while those compressed in LAC andβ-CD slightly increased their
density by around 3% Xanthan gum pellets comprising diclofenac
sodium experienced a porosity reduction of 65% while pellets
comprising ibuprofen showed porosity reduction by approximately
49% An explanation for this observation arises from the hypothesis
that, during compression, the primary particles within the pellet
structurefind new relative position thus affecting the porosity of the
units Diclofenac sodium, the model drug of smallest particle size and
TCP, the filler of smallest particle size, resulted in pellets more
susceptible to reposition, higher degree of compression and higher
densification The results of these studies indicated that the porosity
of the pellets, ruled by the characteristics of the type offiller in their
composition, was a key factor influencing the tensile strength of the
tablet In addition, it was observed that tablets of higher total porosity
were of higher tensile strength This observation was not in
concurrence with the previous studies [14–18] which indicated
almost independence of the original porosity of the particles and
the total porosity for agglomerates of the same composition but of
different porosities Here, the total tablet porosity was found related
with the intra-granular porosity and the mechanical tensile strength
of the pellets The compression process of diclofenac sodium matrix
pellets, which were of higher intra-granular porosity and degree of
densification, than ibuprofen matrix pellets resulted in an extensive
deformation of the units followed by an extensive decrease of porosity
thus leading to compacts of low porosity and high tensile strength
The release of the model drug from all types of matrix pellet
formulations was immediate since pellets comprising the specified
amount of xanthan gum (16% w/w) could not sustain drug release
over the experimental time It was also noteworthy that the tablet
made of matrix pellets did not function as multiple-unit particulate
system (MUPS) and remained as monolithic system
To protect drug-containing pellets from damage during tableting
and avoid segregation, Pinto et al.[35,36]and Lundqvist et al.[37]
developed a system, in which the drug-containing pellets were mixed
with certain amount of soft pellets, which cushioned the drug pellets
during the tableting procedure, with the aim of minimizing damage of
the drug-containing pellets In both works, the authors also included a
third type of pellet to induce tablet disintegration Pinto et al.[35,36]
prepared three different types of pellets by extrusion/spheronisation:
indomethacin (model drug) pellets, disintegrating pellets comprising
barium sulfate and deforming pellets of glyceryl monostearate (GMS)
as cushioning agent and tableted the mixture of these pellets The
compressed tablets showed ability of releasing their intact pellets in a
disintegration or dissolution medium and provided similar
dissolu-tion profile as that of non-tableted pellets The statistical experimental
design revealed high dependence of properties of tablets on the
amount of barium sulfate and GMS present A minimum amount of
50% w/w barium sulfate was required for quick disintegration of
tablets; whereas 25% w/w GMS was essential to provide cushioning
effect to the pellets However, the influence of physical properties of
the soft and hard, drug-containing pellets, on the mechanism of tablet
formation, cushioning and detailed requirement for mechanical
characteristics required from mixture of these pellets is not fully
studied Salako et al.[38]investigated the two types of pellets such as
soft (deforming pellets) and hard (disintegrating pellets) used by
Lundquist et al.[37]in terms of their physical properties in order to
identify, how the proposed system worked The surface tensile
strength of the hard and soft pellets was measured before and after
tableting The application of small pressure (2.89 MPa) to soft pellets did not significantly alter the surface tensile stress of the pellets, suggesting that deformation did not cause majorflaws inside the pellets, but a small drop in the Weibull modulus was observed which indicated that pressure led to some cracks at the surface of the pellets
A further increase in tableting pressure (5.99 MPa) formed a coherent network of deformable pellets in tablet and it was complemented by a significant drop in surface tensile stress, and Weibull modulus also dropped markedly The surface tensile strength of hard pellets was more thanfive times larger than that of soft pellets Uncompacted hard pellets had a higher resistance to fracture and were less brittle than soft pellets, as demonstrated by large value of Weibull modulus During compaction, pellets are constrained to fail mainly in indirect shear due to a radial principal stress induced by neighboring pellets
[39] It was found that agglomerate shear strength of hard pellets (11.94 MPa) was only half of the value obtained for soft pellets (21.59 MPa) This again confirmed that soft pellets are more brittle than hard pellets By observing the laser light reflection patterns of soft and hard pellet compacts, it was concluded that hard pellets are more deformable than the soft pellets Hard pellets were more resistant to crack propagation, but cracks andflaws were formed if a threshold tableting pressure is reached Assuming a mixture of both the types of pellets it appears as though a coherent network of soft pellets could prevent such damage of hard pellets but only if it is formed at tableting pressure below the critical value for the hard pellets or if a sufficient amount of soft pellets are added to cushion the hard pellets during application of load For the studied set of soft and hard pellets, the critical tableting pressure appeared to be at about
9 MPa, while sufficient amount of cushioning, according to the Lundqvist et al.[37], was provided by about 40% of soft pellets The above study did not fully mention the influence of adjacent pellets of different mechanical strength on behavior of drug pellets during compression Tunon et al.[40]investigated that the deformation and densification during compression of one type of granules is affected by adjacent granules of a different porosity, corresponding to different mechanical strength Three mixtures were prepared, each consisting
of two types of MCC pellets (intermediate porosity study pellets plus low, intermediate or high porosity surrounding pellets) in the proportion of 1:7 The mixtures were compressed and the study pellets were retrieved and analyzed in terms of porosity, thickness, surface area and shape SEM micrographs revealed changes in shape
of the study pellets with compaction and the influence of porosity of the surrounding pellets on these changes Excipient pellets with high porosity resulted inflattened but relatively regularly shaped retrieved study pellets Excipient pellets with lower porosity resulted in study pellets with a more irregular shape: the study pellets had regularly positioned cavities or indentations caused by the surrounding excipient pellets rather than increased flattening This type of irregularity was most pronounced for study pellets that had been compacted with excipient pellets of lowest porosity (higher mechan-ical strength) Two different modes of deformation (here referred to
as mode I and mode II respectively) can, in generalized way, explain the deformation behavior of granules [40] Mode I deformation describes a local change in the geometry of the external surface of granules (due to low compression pressure) in order to conform the external surface of adjacent granules (i.e no change in bulk dimension) Mode II deformation describes a change in the main dimension of the granules (due to higher compression pressure) primarily expressed as aflattening of their bulk (bulk deformation with significant granule densification) The type of shape change reported in their study could be described as extended mode I deformation i.e local deformation leading to conformation with adjacent granules surface in such a way that indentation into the study granules were formed It was concluded that the incidence and character of mode of deformation occurring in given granules will be dependent on the mechanical properties of adjacent granules When
Trang 6the surrounding granules have a higher mechanical strength than the
study granules, indentation will occur
The physico-mechanical and release properties of thermal-treated
(cured) pellets containing various percentages of ibuprofen,
Eudra-git® RSPO and RLPO were studied and compared with those of
uncured pellets in an attempt to identify those pellets which are able
to withstand the compression process[41] The pellets containing
different ratio of ibuprofen (40, 60 and 80) and various ratio of
Eudragit®RSPO/RLPO (0, 50 and 100) were prepared, using factorial
design, by extrusion and spheronisation technique The pellets were
cured in oven at 60 °C for 24 hours The evaluated responses were
crushing strength or yield point, elastic modulus and mean
dissolu-tion time (MDT) of pellets Their previous study[42]showed that all
uncured pellets had brittle behavior under the mechanical tests and
were found to break into fragments This study showed that the cured
pellets containing 40% or 60% drug exhibited plastic deformation
without any fracture under mechanical tests However, the cured
pellets containing 80% drug showed brittle behavior similar to
uncured pellets The uncured pellets containing 40% and 60%
ibuprofen exhibited elastic modulus between 71 and 133 MPa[42],
while after curing the elastic modulus decreased to 45 to 76 MPa This
indicated reduced rigidity and high tendency to plastic deformation
for these pellets SEM of surface of tablets prepared from cured pellets
revealed that pellets remained as coherent individual units in tablet
even after compression and the boundaries between individual
pellets were readily observable However, the surface of tablets
made from uncured pellets showed a uniform structure and no
distinct boundary was observed indicating fusion of broken pellets
into each other The transition of pellet behavior (for those containing
40% or 60% drug) from brittle to plastic upon curing could be
attributed to the softening of the polymer and shift of polymer
structure from glassy to a rubbery state The curing process also
retarded the drug release from pellets and increased MDT The MDT of
uncured pellets was in the range of 33.83 to 63.94 min but after curing
it increased to a range of 61.61 to 153.84 min A similar retarding
effect upon curing was reported for the release of indomethacin[43],
diclofenac [44] and ibuprofen [45] from Eudragit® based matrix
tablets These effects could be attributed to the softening of polymer
due to the polymer chain movement and inter-diffusion of Eudragit®
chain in the pellet matrix following curing This resulted in better
coalescence of the polymer particles and formation offine polymer
network amongst other particles that surrounds and entangles the
drug SEM of surface of uncured pellets revealed that the individual
polymer particles could be easily distinguished However, in cured
pellets the matrix structure was formed of coalesced polymer
particles Sufficient curing probably softens the polymer causing it
tofill in the interstices thereby reducing porosity The same findings
were reported by Kojima and Nakagami[46]and Kidokoro et al.[45]
in the case of ethylcellulose pellets and Eudragit®tablets respectively
Marked reduction in porosity of Eudragit®matrixes upon curing was
reported by Azarmi et al.[47]and accounted for decrease in drug
release rate Overall results of this study concluded that thermal
treatment (curing process) should be taken into consideration before
compression of acrylic copolymers and other polymer matrix pellets
prepared by extrusion and spheronisation
2.3 Effect of nature of granulationfluid
In addition to the incorporation of other co-diluent excipients, the
nature of granulationfluid can also affect the compactability of MCC
pellets The compaction behavior of pellets prepared by extrusion and
spheronisation process based on various compositions, such as MCC,
lactose, GMS, water, ethanol and glycerol were investigated[48] The
starting formulation in this work was a mixture of MCC: water (1:1)
The pellets from this starting formula could not form tablets
presumably due to the confinement of the MCC fibers, the strong
and elastic nature of the pellets which reduced the connectivity between each other during compaction To change the mechanical properties of MCC pellets, 40 and/or 60% w/w of MCC was replaced by lactose which is harder and more brittle or GMS which is soft and ductile material Additionally, 40 and/or 60% w/w of the water was replaced by ethanol to produce higher porosity or glycerol to provide different mechanical properties GMS containing pellets had the lowest mean rugosity values which further decreased with increase in GMS content in pellets indicating greatest deformability SEM revealed that the pellets seemed to beflattened and fully merged with each other to produce smoother surface profile MCC pellets produced with 40% w/w ethanol had the highest total porosity which increased with increase in their proportion to 60 % w/w in the liquid binder The mean rugosity values decreased with increase in ethanol content in the liquid binder from 40 to 60% w/w, hence total porosity The lactose containing pellets had the greatest mean rugosity values which increase with increase in proportion from 40% to 60 % w/w SEM revealed that pellets containing glycerol did not cohere with each other and the space between them was distinct and deep Thus, considerable deformability of these pellets was dominated by prominent grooves between pellets The main reason could be the retention of liquid glycerol in the pellets after drying, which could have reduced the coherence between the pellets even after their compression by a great pressure The authors concluded that surface roughness parameter obtained from non-contact laser profilometry could determine the plastic deformability of pellets during compac-tion In another study, theophylline:MCC (1:10) pellets were prepared
by extrusion/spheronisation using ethanol/water mixture in varying ratio as granulatingfluid[49] Increasing the amount of water in the mixture resulted in harder and less porous pellets and slow drug release Water-granulated pellets were not very compressible; whereas pellets prepared with 95% ethanol had excellent compress-ibility This was attributed to the weaker character of the ethanol-granulated pellets, which ruptured during compaction, forming new surfaces for bonding The stronger, water-granulated, pellets resisted rupturing and fewer surfaces were available for bonding as shown in photomicrographs
2.4 Effect of drying methods The porosity of pellets can be easily affected by the drying technique Bashaiwoldu[50,51]compared the effects of four different drying techniques, namely: freeze-drying,fluid-bed drying, hot-air oven drying and desiccation with silica-gel on the structural and mechanical properties of 1.0 to 1.8 mm size fraction MCC pellets prepared by the process of extrusion/spheronisation with a 40% solution of ethanol in water in terms of size, density/porosity, surface area, surface tensile strength, shear strength, deformability, linear strain, elastic modulus, Weibull modulus, compressibility and com-pactability To overcome the problem of producing weak tablets from pellets prepared from water and MCC, the pellets were produced with
a 40% solution of ethanol in water as shown by Johansson et al.[14]to produce stronger tablets In all the cases, the drying process was continued until thefinal moisture content of the pellets was less than 5% w/w, which is equivalent to moisture content specified for MCC Based on the different rate of moisture removal, means of heat and mass transfer, and static or dynamic nature of the bed, the different drying techniques produced pellets of different structural and mechanical properties The most crucial of these was the porosity as
a result of different extent of shrinkage of the pellets The rapid evaporation of water as a result of turbulent motion of thefluidized pellets (fluid-bed) and the direct evaporation of the expanded ice (freeze–drying) suppressed the shrinkage of pellets during drying to produce pellets of higher porosity and of greater mean diameter On the other hand, the evaporation of thefluid took place in a very slow manner when drying by oven or desiccation with silica-gel was done
Trang 7This could be the reason for the greater shrinkage and lower porosity
of the pellets in latter techniques As a result, the strength,
deformability and strainability of pellets varied The order of increase
in pellet strength starting from the weakest was freeze-dried,
fluid-bed dried, oven dried to those pellets dried by desiccation with
silica-gel The arrangement of pellets in their strength was in reverse order
to their total porosity Thus, greater the porosity, weaker the pellets
Dryer et al.[52]made a similar observation that tray-dried ibuprofen
and lactose pellets are stronger, less elastic, and more brittle than
theirfluid-bed dried counterparts Thus, the fluid-bed drying process
was recommended for pellets that are intended to be compressed
[52] Bataille et al [53] had also found that less porous pellets
produced by oven drying have a higher strength than the porous
microwave dried pellets Berggren and Alderborn[54]found that the
drying rate during static drying clearly affected the physical
properties of pellets An increased drying rate resulted in more
porous MCC pellets Moreover, the drying rate also affected the
deformability of the pellets and their ability to form tablets An
increased drying rate generally resulted in more deformable pellets
during tableting
3 Tableting of coated pellets
Coated pellets are chosen as drug units when high standards with
regards to reproducibility of drug release and drug safety has to be
assured [55,56] A common way to design oral modified-release
system is to coat spherical granules (pellets) with a polymer that
regulates their drug release rate Such reservoir pellets can be
incorporated into hard gelatin capsules or compacted into
multiple-unit tablets Compression of polymer-coated beads into tablets raises
concerns regarding the loss of integrity of the polymer coat following
compression and hence its functionality The polymer coat must have
the right combination of strength, ductility, and thickness to
withstand the forces generated during compaction without rupturing
This section discusses the key variables affecting the compaction and
performance of coated pellets (reservoir-type drug delivery systems)
including the different types of polymer coating, the properties of
pellets core and various types of tableting excipients
3.1 Nature and amount of polymers
There are numerous reasons for whichfilm coatings are applied to
pellets: modified-release, taste masking, improved stability, elegance,
and mechanical integrity can be mentioned as examples Polymers
used in thefilm coating fall into two broad groups: cellulosic and
acrylic polymers[57,58] The acrylic polymers are marketed under the
trade names of Eudragit®or Kollicoat® The major cellulosic polymer
used for extended-release is ethylcellulose These polymers can be
formulated as aqueous colloidal dispersions (e.g latexes or
pseudo-latexes) and organic solutions The polymeric particles have to be
mechanically deformable to formfilms under specified conditions
This is achieved at a softening temperature[59], which corresponds to
a sharp increase in polymer chains mobility[60], hence viscousflow,
which eliminates the boundaries between adjacent polymer particles
to complete coalescence[61] In addition to the possible incomplete
fusion of the colloidal particles during the coating process[62], the
residual internal stresses within thefilm coating created by shrinkage
of the film upon solvent evaporation and the differences in the
thermal expansion of the coating and the substrate, can produceflaws
and cracks in thefilm coating[63] Moreover, the drastic shape and
density changes as well as the friction and impact of the die and punch
surfaces during tableting of coated pellets could compromise the
integrity of coat and hence the controlled release property Thus, the
mechanical properties of the polymeric film and its response to
stresses of different types must be studied in order to investigate its
suitability for the coating of pellets to be compressed This section
deals with key variables involved in the polymer coatings for modified-release pellets such as delayed-release and extended-release and their compression into tablets
3.1.1 Cellulosic polymers Most studies on the compaction of pellets coated with ethylcellu-lose revealed damage to the coating with a loss of sustained-release properties This is mainly due to the weak mechanical properties of ethylcellulose Ethylcellulosefilms cast from the plasticized pseudo-latexes, Aquacoat®and Surelease®, were very brittle and weak with low values for puncture strength and elongation (b5%) [64].The mechanical properties of Aquacoat®films were not strengthened with different types of plasticizers (brittle, with elongation valuesb2% in most cases) Curing of the pseudo-latex-cast ethylcellulosefilms also had minimal effects on their mechanical properties[64]
Maganti and Celik[7]observed significant changes between the compaction properties of the powder and pellet forms of the same formulation In their study (already discussed in Section 2), the powder formulations deformed plastically and produced strong compacts, whereas their pellet forms exhibited elastic deformation and brittle fragmentation which resulted in compacts of lower tensile strength Later, they reported that the addition of Surelease®as a coating material at the level of 10, 15 and 20% w/w altered the deformation characteristics of uncoated pellets from being brittle and elastic to plasto-elastic properties by introducing bonds between substrate and coating material [65] An increase in coating level, however, caused a decrease in tensile strength (10%N15%N20%N uncoated pellets), a reduction in the yield pressure of the pellets and
an increase in the elastic recovery upon ejection Increasing the coating level reduced the pressure necessary to obtain the same in-die porosity, indicating an easier compressibility of the coated pellets The 10% coated pellets showed tensile strength higher than other coated pellets The authors explained that there was formation of bonds between substrate and coating material i.e., binder–binder bonding, binder–substrate bonding and substrate–substrate bonding between fragmented neighboring pellets If the coating level was increased, binder concentration got increased that led to greater binder–binder than binder–substrate bonding responsible for tensile strength The polymer caused an additional expansion because of its elastic characteristics The ability of the pellets to deform, both plastically
or elastically, increased with increasing coating level Increasing the punch velocity resulted in a reduction in the tensile strength of the compacts and an increase in both yield pressure and elastic recovery values This may be explained by the combination of low overall plasticity (which is time-dependent, that is unable to produce adequate inter-particle bonding during compression) due to high punch velocities and relatively high elasticity (that breaks weak bonds formed during compression) during decompression and ejection phases The punch velocity dependence of these variables was greater with pellets coated with higher coating levels The results of dissolution studies revealed that the coated pellets lost their sustained-release properties during compaction, regardless of the coating level and the compaction pressure This was attributed to the formation of cracks within the coating and to the fragmentation of the pellets
Disintegrating tablets from sulfamethoxazole pellets coated with cellulose acetate phthalate described by Takenaka et al.[66], liberated more than 10% of drug within 2 h in artificial gastric fluid and thus did not confirm to the pharmacopeial requirements Lehmann et al.[67]
developed disintegrating tablets containing enteric-coated ASA or indomethacin pellets coated with Eudragit®L and liberating less than 10%w/w of the active ingredient within 2 h in 0.1 M HCl These tablets confirmed to the pharmacopeial requirements
In order to overcome the brittle character of ethylcellulose, multilayered beads consisting of approximately ten alternative layers
of acetaminophen and polymer coats (Aquacoat®) with an outer layer
Trang 8of mannitol/MCC as an additional cushioning excipient[68,69]were
prepared The idea behind this concept was that when the
multilayered beads were compressed into tablets the outermost
layers would absorb the pressure and fracture to provide immediate
release, while the innermost layers would be protected from fracture
and provide sustained drug release SEM micrographs revealed that
there was significant deformation of the beads that led to
densifica-tion of the drug/polymer layers upon compacdensifica-tion, discrete beads
could be clearly distinguished within the tablet However, cracks in
some of the layers could also be observed Drug release patterns also
indicated that polymer layers were still ruptured during compression
Spray coating of the cushioning excipients onto beads provided an
effective way to circumvent segregation issues associated with mixing
of the polymer-coated beads and powdered or spherical/ nonspherical
cushioning excipients At higher compression forces and coating
levels in excess of 15%, non-disintegrating materials with useful
sustained-release properties were obtained It was concluded that
different amounts or ratios of active ingredients could be“buried” in
the core or applied only to the surface layer to obtain a preferred drug
release rate and those layered beads could be further layered with
cushioning excipients such as MCC and mannitol to avoid segregation
problem during compression
3.1.2 Acrylic polymers
When compared to ethylcellulose films, films prepared from
acrylic polymers are moreflexible and therefore more suitable for
coating of pellets intended to be compressed into tablets[64] Small
particles such as crystals, granules and pellets of a particle size in the
range of 0.3 to 1.2 mm were coated with aqueous dispersions of
methacrylic acid and methacrylic acid ester copolymers (Eudragit®
RL30D, RS30D and NE30D) for sustained-release properties and
compressed into fast disintegrating tablets[70] Admixture of 25 to
50% of tableting excipients such as MCC, sorbitol, starch and sodium
carboxymethyl starch asfillers, and disintegrants were necessary to
facilitate faster disintegration of the tablets; the function of these
substances were bothfilling of the interspaces, as well as separation
and protection of the coated particles during compression
Multi-particulates coated withflexible polymers (Eudragit®NE 30 D and
plasticized Eudragit® RS/RL30D) could be compressed without
significant damage to the coating The authors found that elongation
at break of 75% or more was sufficient for compression of coated
particles without or with very small damage of the release-controlling
membrane Films of Eudragit® NE30D were very flexible This
dispersion had a minimumfilm-forming temperature of around 5 °C
and did not require addition of plasticizers in content to the other
dispersions evaluated The molecular structure of the polymer, which
is based on acrylic esters, indicates the lack of strong interchain
interactions (e.g hydrogen bonds), thus explaining the flexible
character of the polymerfilms The film of Eudragit®NE30D showed
high elongation at break of approximately 600% which wasflexible
enough to withstand deformation forces during tableting Formation
of cracks or pores were not detected in SEM Very little difference in
drug release was observed between the compressed granules and the
non-compressed granules, containing theophylline coated with
Eudragit® RL/RS dispersions Owing to different permeability but
unlimited miscibility of Eudragit® RL30D and Eudragit® RS30D
dispersions, a wide range of permeability could be established such
that the system could be adapted to the diffusion properties of many
drugs in a narrow range offilm thickness These polymers showed
insufficient elongation at break of less than 50% when no or only 10%
plasticizer was added With more plasticizer of approximately 20%
calculated as polymer weight in the film, elongation at break
increased up to 80 to 300% which was sufficient to withstand the
mechanical stress of compression so that the release pattern of
disintegrating tablets was similar or nearly same as for the
uncompressed particles
Lopez-Rodriguez et al studied the compression behavior of different acetylsalicylic acid (ASA) formulation such as ASA crystals, ASA pellets and ASA coated (with DBS plasticized Eudragit® RS) pellets with and without MCC[71] They used elastic recovery and force-displacement curve to evaluate compression behavior of such formulation The compression data showed that ASA crystals, ASA pellets and ASA coated pellets with MCC had similar compression characteristics, while ASA coated pellets without MCC had very different compression behavior Force-displacement curves of the four different formulations also confirmed that coated pellets without MCC had different compression behavior than other formulations Compression of coated pellets without MCC could lead to matrix tablets where thefilm layers came into intensive contact with one another and fused during compression The drug release profile of the pellets before and after compression was also studied MCC concentrations higher than 15% w/w were required to obtain tablets
of coated pellets with drug release properties similar to the coated pellets before compression
Small particles such as ASA crystals and indomethacin pellets of particle size in the range of 0.3 to 1.2 mm were coated with Eudragit®
L30D55 for resistance to release in gastricfluid and compressed with suitable tableting excipients into fast-disintegrating tablets[70] The enteric acrylic latex, Eudragit®L30D55 resulted in weak and brittle films (elongation at break of b1%) A possible explanation could be strong interchain hydrogen bonding caused by the presence of carboxyl groups SEM showed that there were cracks in the range of
5 to 50 µm in coated pellets after compression into fast disintegrating tablets The drug release in simulated gastricfluid during 2 h was approximately 20-30% due to broken/crackedfilm Such preparations cannot meet the requirements of enteric formulations and are therefore of limited value in tableting of coated particles The authors avoided the compression-induced cracks/damage in Eudragit®
L30D55film by mixing the enteric polymer with flexible Eudragit®
NE30D A mixing ratio of 1:1 resulted in an elongation at break of the films of 112% and a mixing ratio 8:2 together with 10% polysorbate resulted in an elongation at break of 93% Disintegrating tablets prepared from indomethacin and ASA coated with such heterogonous films liberated less than 10% w/w of drug within 2 h in simulated gastricfluid It can be concluded that by mixing Eudragit®L30D55 with flexible Eudragit® NE30D, enteric coatings of acceptable mechanical stability and sufficient flexibility could be prepared The abovefinding was confirmed by Shimizu et al.[72–74] They prepared lansoprazole fast disintegrating tablets in which lansoprazole pellets were coated with the mixture of Eudragit L30D55 and Eudragit NE30D
in a ratio of 9:1 with 20%(w/w) TEC as plasticizer Dashevsky et al.[75]
also confirmed the above studies by coating ASA crystals with a mixture of Kollicoat®MAE30 D and Kollicoat®EMM30D ASA pellets which were coated with the enteric polymer dispersion Kollicoat® MAE 30 DP and 10% w/w TEC as plasticizer lost their enteric properties after compression into tablets Mixing the enteric polymer with the highlyflexible Kollicoat®
EMM30D in the ratio of 70/30 with 10% w/w TEC could eliminate the loss in enteric properties
However, with bisacodyl pellets, the drug release with these mixedfilms did not fulfill the pharmacopeial requirements for enteric dosage forms[76] Films made from Eudragit®L30D55 were so brittle
to adjust to the deformation of pellets during compression that an increase in coating thickness from 12.5 to 25% did not avoid thefilm rupture However, since rupturing is a time-dependent process, at least short-time elasticity would improve with the thickness of more elastic coatings The authors applied thicker coating from 12.5 to 25%
of the mixture containing Eudragit®L30D55 and Eudragit®NE30D in the ratio of 1:1 on the bisacodyl pellets The liberation of bisacodyl in 0.1 M HCl from this mixedfilm was approximately 4% w/w of the total bisacodyl content But these mixed coatings did not dissolve and release sufficient bisacodyl between pH 6.8 and 7.5 and did not fulfill the pharmacopoeial requirements for enteric dosage forms Two new
Trang 9polymers showing high elasticity combined with sufficient
dissolu-tion in the pH range 6.8 to 7.0 have been developed by Röhm for the
compression of coated pellets[77] The ethyl acrylate monomer was
replaced with methyl acrylate or with methyl
acrylate/methylmetha-crylate in order to provide moreflexible films, which would allow the
compression without damage of the polymeric coating A copolymer
of methacrylic acid: methacrylate (20:80) dissolves at pH 6.4, while a
copolymer composed of methacrylic acid: methacrylate:
methyl-methacrylate (10:65:25) dissolves at a higher pH, value of 7.2 These
new polymers had an elongation at break in excess of 50% but
the addition of 5 to 10% TEC resulted in elongation values up to 300%
[77] Pellets coated with 25% w/w of one of these new polymers
liberated only 4.5%w/w bisacodyl in acidic media and liberated 100%
w/w bisacodyl in phosphate buffer pH range between pH 6.8 and 7.2
within 45 min
Debunne et al investigated the influence of formulation and
compression parameters on the properties of tablets (tablet
mechan-ical strength, friability and disintegration time) containing
enteric-coated piroxicam pellets and on the integrity of the enteric coat after
compression [78] They studied the influence of three
formu-lation parameters such as amount of coating material (ratio of
Eudragit®L30D55/Eudragit®FS30D at different coating levels from 5
to 15% w/w) and the enteric-coated pellets/cushioning pellets ratio
and one process parameter i.e compression force using a D-optimality
experimental design The full experimental matrix consisted of 735
experiments The results of experimental matrix revealed that the
properties of tablets mainly based on the ratio of coated pellets/waxy
cushioning pellets in the tablet Increasing the proportion of coated
pellets versus cushioning pellets resulted in a decrease of the
mechanical strength The deformable waxy pellets formed a
contin-uous matrix in which the coated piroxicam pellets were embedded
However, incorporation of the hard piroxicam pellets disrupted the
matrix and resulted in a reduction of the number of bonding sites and
bonding strength between these pellets This explained the lower
tablet mechanical strength and disintegration time and higher
friability when the number of piroxicam pellets increased in the
tablet The dissolution test in 0.1 M HCl showed no piroxicam release
from any tablet formulations Flexibility and deformation properties
of the coatings are determined by the amount and type of plasticizer,
the elongation break of the polymer and the thickness of the polymer
film Eudragit®FS30D, (poly (methylacrylate: methylmethacrylate:
methacrylic acid, 7:3:1)) a polyacrylate 30% dispersion was
incorpo-rated in these formulations because of its higher elongation break (up
to 300% in combination with 10% TEC)[67]compared to Eudragit®
L30D55 (20%) Wagner et al [79] also showed that the use of
Eudragit®FS30D at a high coating level decreased damage to the
pellet coatings in the tablet Increasing the thickness of the coating
normally increases the resistance against rupture of the film
However, regardless of the composition and the amount of coating,
the integrity of entericfilm coat of piroxicam pellets was maintained
during compression It can be concluded that by incorporation of
Eudragit® FS30D in the Eudragit® L30D55, enteric coatings of
acceptable mechanical stability and sufficient flexibility could be
prepared However, Beckert et al reported that it was possible to
compress enteric-coated pellets into tablets without significant
damage using Eudragit®L30D55 at 35% level and propylene glycol
at 20% level as plasticizer[80] This was also confirmed by Lefranc et
al They reported similarfindings for enteric-coated ASA pellets[81]
3.2 Effect of plasticizers
Dashevsky et al investigated[75]the effect of compaction on the
drug release from the compacts of coated pellets containing
propranolol hydrochloride In their study, pellets were coated with
aqueous polyvinyl acetate dispersion, Kollicoat® SR30D and with
ethylcellulose pseudo-latex dispersion (Aquacoat®ECD30) and were
compacted with external additives of MCC The propranolol hydro-chloride release from compressed pellets, which were coated with Aquacoat®, was significantly faster than from the original pellets irrespective of the compression force or the pellet content of the tablets This could be explained by the weak mechanical properties of ethylcellulosefilms, which ruptured during compression Kollicoat®
SR30D coated pellets usually neither require plasticizer for film formation nor curing step (thermal after-treatment) because of the low minimumfilm formation temperature The pellets also have a pH-independent drug release and are easily processed[82] Plasticizer-free Kollicoat®SR coatings were too brittle (elongation approximately 1%) and ruptured during compression Theflexibility of the coatings was dramatically improved by the inclusion of a plasticizer, elongation values up to 137% were obtained with relatively low amount of plasticizer (10% w/w triethyl citrate (TEC)) The addition of only 10% TEC to Kollicoat®SR30D resulted in almost unchanged drug release profiles at different compression forces because of the improved mechanical properties It was concluded that Kollicoat®
SR 30 D, an aqueous colloidal dispersion of polyvinyl acetate, with small amount of plasticizer (10% w/w, TEC) resulted in flexible coatings and was a suitable polymer for coatings of pellets, which were compressed into tablets This study was also confirmed by Sawicki et al.[83] These authors investigated the effect of compaction
on floating pellets of verapamil hydrochloride (VH) which were coated with Kollicoat® SR30D They selected Kollicoat® SR30D stabilized with povidone and sodium lauryl phosphate for coating
on the basis of data from literature[84] Those data indicated that this kind of dispersion could ensure formation of film having proper resistance properties[85] In these experiments three plasticizers were employed: propylene glycol (PPG), TEC and DBS (all at concentration of 10% w/w) The pellets were coated at two different levels with Kollicoat®SR30D, at 35 µm and 50 µm thickness It was found that VH release from pellets coated withfilms of the same thickness, but containing different plasticizers was considerably different DBS and TEC slowed down diffusion to a higher degree owing to their low solubility in water (0.01 and 5.5 to 6.3%) as compared to PPG[86] Photomicrograph showed that pellets coated with 35 µm polymer thickness deformed as a result of compression Therefore VH release from these tablets was considerably faster than from uncompressed pellets The increase in drug release rate was not attributed to rupturing of polymericfilm, but to thinning of film since
50 µm thickness of film prevented its damage caused by compressibility
3.3 Effect of pellet size Bechard and Leroux investigated[87]the effect of compaction on the drug release from the compacts of varying mesh cuts of coated microspheres containing chlorpheniramine maleate (CPM) In this study, microspheres were coated with an ethylcellulose pseudo-latex dispersion (Aquacoat®) plasticized with 24% dibutyl sebacate (DBS) and mesh cuts of 20/30 (590 to 840 µm), 30/40 (420 to 590 µm) or 40/
60 (250 to 420 µm) were compacted with external additives such as MCC, dicalcium phosphate anhydrous or compressible sugar The workers reported that massive film fracture occurred at high pressures regardless of the microsphere particle size or the external additives used, and total loss of the controlled-release characteristics was observed They pointed out that smaller particles appeared to be more fragile than larger ones This was attributed to the differences in film thickness which was found to be 15 µm for the 40/60 mesh microspheres as opposed to 20 to 25 µm for the 20/30 and 30/40 mesh pellets These results are in agreement with a study where potassium chloride (KCL) crystals coated with an organic solution of ethylcellu-lose were more resistant to compaction than crystals coated with the pseudo-latexes, Aquacoat®or Surelease®plasticized with 20% DBS
[88] The sustained-release properties of the pseudo-latex-coated
Trang 10crystals were lost after compaction Possible reasons given were
incomplete fusion of the colloidal particles, the pressure of additives
in the coating and migration of KCL into thefilm during the coating
process However,films deposited from organic solvents were found
to be mechanically stronger during compaction than coatings
prepared from the pseudo-latexes [64] Tablets containing 40/60
mesh coated pellets were introduced in a convection oven set at 75 °C
for 24 hours to obtain retardation in the drug release[88] The storage
at elevated temperature resulted in a decrease in drug release after
30 minutes, 55% of CPM was released for the tablet dried at 75 °C as
opposed to 85% for the non-heated material The results showed that a
certain amount offissures were sintered by exposing the compacted
pellets to a temperature above film glass transition temperature,
which is about 43 to 44 °C for afilm of that composition[89] The
compaction of diltiazem hydrochloride pellets coated with
ethylcel-lulose resulted in a faster drug release irrespective of the formulation
used when compared to the release from non-compressed pellets
[90] The tensile properties of freefilms as a function of plasticizer
were measured The elongation varied between 0.93 and 4.28% for
different plasticizers This is obviously too low to result inflexible
films, which deform and do not rupture during compression
3.4 Pellet core
As discussed above, without sufficient flexibility of the film, the
coating could rupture during compression and the modified-release
properties would be lost Besides coating, the pellet core also will
affect the compaction behavior of the coated pellets The structure of
both the pellet core and the coating are inter-related and it is
suggested that, as a general rule,film coating and pellet core should
have similar properties [91] There are, however, contradictory
recommendations as to whether the pellets should be hard and
non-deforming, making them better able to withstand coating
rupture [76] or plastically deformable, so as to accommodate a
possible change in shape when compacted, and recover after
compression without damage to the coating[25]
Although the literature contains several studies on compaction of
coated pellets, there are few on the influence of properties of pellet
core on drug release from compacted reservoir pellets Ragnarsson et
al.[92]and Haslam et al.[93]have found drug release from small,
coated pellets to be less affected by compaction, than larger ones
When Beckert et al.[76]compacted Eudragit®L30D55 coated pellets
of different crushing strengths with different excipients, they
concluded that hard pellets were able to withstand compression
forces as they deformed to a lesser degree and thefilm coatings were
less susceptible to rupture Minimal damage to coated pellets was
found when the elastic and tensile properties of the coated and the
uncoated pellet were similar
As per discussion inSection 2, it was found that uncoated pellets
formed from MCC, deform and become denser during compression It
was also mentioned that an increase in original porosity will increase
the degree of deformation and densification which the pellet undergo
during compression It was also described that extragranular factors,
such as the properties of pellets that surround the pellets of interest,
may affect its compression behavior Tunon et al investigated the
influence of intra-granular porosity of pellet core, on the densification
and deformation behavior and subsequent effect on drug release from
compacted reservoir pellets [94] They prepared pellets of low,
medium and high porosities, consisting of MCC and salicylic acid by
extrusion/spheronisation and spray coated with ethanolic solution of
ethylcellulose Lubricated reservoir pellets were compressed and
retrieved by deaggregation of the tablets The retrieved pellets were
analyzed for porosity, thickness, surface area, shape and drug release
The drug release profiles were characterized in terms of the time for
half the amount of drug actually detected to appear in solution (t50%)
and by statistical moment analysis in terms of mean dissolution time
(MDT) The uncoated pellets released the drug quickly but there was marked dependence on pellet porosity, i.e increased porosity gave quicker drug release Milli et al.[49]also confirmed these results that the drug was released more quickly from pellets prepared with ethanol as granulation liquid, compared to when water was used Coating prolonged the drug release considerably However, drug release was prolonged differently, depending on porosity, i.e increased pellet porosity reduced the prolongation time in t50%, and MDT The suggested possible explanations were: 1) porous pellets were more friable and drug particles could be abraded from the pellet surface and incorporated into the film coating during the coating process [49], and 2) coating on more porous pellets was more unevenly distributed due to increase in surface roughness with greater pellet porosity[18] MDT of uncompacted reservoir pellets was found to depend on pellet surface area in such a way as to decrease with increasing surface area In this study the increase in specific surface area was greatest for high porosity reservoir pellets and smallest for low porosity, while inversely, the change in drug release was greatest for low porosity pellets and least for pellets of high porosity The results indicated that compacted pellets of high original porosity were highly densified and deformed, while drug release was unaffected, whereas for compacted low porosity pellets the drug release rate was markedly increased while there was only slight densification and deformation The authors suggested the following explanations for less deformable pellets that were more affected in terms of changes in compression-induced drug release Firstly, since the highly porous pellets also densified significantly during compaction, the ability of the coating to adapt to both shape and volume changes in the core may indicate that the coating is also compressed and thus rendered less permeable during compaction, which was confirmed with SEM studies SEM showed that there was
no tendency for the polymerfilm to become convoluted and it seemed that thefilm continued to coat the deformed pellets firmly even after compaction Secondly, for the low porosity pellets, a larger proportion
in terms of number of pellets came in contact with the punches and die during compaction It was concluded that the use of highly porous pellets was advantageous, in terms of preserving the drug release profile after compaction, compared to pellets of low porosity 3.5 Tableting excipients
Various tableting excipients have to be added to assist the compaction of coated pellets The excipients are used tofill the void space between the pellets to be compressed and act as cushioning agent to absorb compression forces Thefiller materials are used for separation of individual pellets to prevent direct contact of pellets (e.g polymer-coated pellets that tend to fuse with each other during compression) by forming a layer around the pellets These inert excipients should also provide protection to the coated particles from rupture and damage during compression The excipients should result
in hard and rapidly disintegrating tablets at low compression forces and should not affect the drug release Besides their compaction properties, the excipients have to result in a uniform blend with the coated pellets, avoiding segregation and therefore weight variation and poor content uniformly of the resulting tablets
3.5.1 Nature and Amount of Excipients Beckert et al investigated the influence of amount and type of excipients such as PEG 6000, Cellactose (which is a loose agglomerate containing 75%α-lactose monohydrate and 25% powdered cellulose), Avicel PH 200 (a granular material of MCC) and Bekapress D2 (DCP anhydrous), when compressed with Eudragit® L30D55 coated bisacodyl pellets [76] At the compression force of 15 kN, the comparison of excipients was made At a pellet level of 10% w/w, there were only marginal differences in bisacodyl liberation between four excipients At 90% w/w pellets, the liberation of bisacodyl was