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.
Journal of Controlled Release 147 (2010) 2–16 Contents lists available at ScienceDirect 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 r e l Review A flexible technology for modified-release drugs: Multiple-unit pellet system (MUPS) Shajahan Abdul, Anil V Chandewar, Sunil B Jaiswal ⁎ P Wadhwani College of Pharmacy, Yavatmal, Maharashtra, 445001, India 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 a b s t r a c t 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 the final dosage form, the multiparticulates are usually formulated into single-unit dosage forms such as filling 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 Introduction Tableting of uncoated pellets 2.1 Compaction of microcrystalline cellulose pellets 2.2 Compaction of microcrystalline cellulose pellets containing other excipients 2.3 Effect of nature of granulation fluid 2.4 Effect of drying methods Tableting of coated pellets 3.1 Nature and amount of polymers 3.1.1 Cellulosic polymers 3.1.2 Acrylic polymers 3.2 Effect of plasticizers 3.3 Effect of pellet size 3.4 Pellet core 3.5 Tableting excipients 3.5.1 Nature and Amount of Excipients 3.5.2 Particle size of excipients 3.5.3 Homogeneity and divisibility of tableted pellets dosage form Conclusions References Introduction Modified-release dosage forms (MRDF) have always been more effective therapeutic alternative to conventional or immediate-release ⁎ 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 doi:10.1016/j.jconrel.2010.05.014 4 7 8 10 10 11 11 11 13 14 14 14 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 S Abdul et al / Journal of Controlled Release 147 (2010) 2–16 stable 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 nondisintegrating 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] Interand 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 the final 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 capsule filling 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 lowpotency, 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 after filling 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 multipleunit 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 illustrates 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-disintegrating matrix during compaction and should disintegrate rapidly into individual pellets in gastrointestinal fluids 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 is a flow 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 parameters influencing performance of tableted multiparticulates Fig Schematic representation of types of MUPS — (a) MUPS comprising of coated pellets, and (b) MUPS prepared from uncoated/matrix pellets 4 S Abdul et al / Journal of Controlled Release 147 (2010) 2–16 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 Fig Flow chart representing factors influencing compaction of reservoir pellets 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 that five 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 compaction process of pellets can be summarized in a four stage model (Fig 3), as follows: 1) volume reduction of the pellets by rearrangement of pellets to fill inter-particle voids 2) volume reduction of pellet bed by local surface deformation involving surface flattening 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 intergranular bonding force is not sufficiently strong to cohere the pellets Fig 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 The numbers I, II, III and IV correspond to the four stages described in the text 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 by flow 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 S Abdul et al / Journal of Controlled Release 147 (2010) 2–16 finding 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 plastic flow 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 deformation and brittle fragmentation 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 compaction/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 formulations 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 S Abdul et al / Journal of Controlled Release 147 (2010) 2–16 matrix pellets in both the studies showed a compression-induced change in shape and marked pellet deformation (i.e pellets flattened) 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 and β-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 structure find 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 of filler 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 dissolution 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 major flaws 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 than five 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 and flaws 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 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 in flattened 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 mechanical 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 a flattening 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 S Abdul et al / Journal of Controlled Release 147 (2010) 2–16 the 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, Eudragit® 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 dissolution 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 but after curing it increased to a range of 61.61 to 153.84 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 of fine 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 to fill 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 granulation fluid In addition to the incorporation of other co-diluent excipients, the nature of granulation fluid 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 be flattened 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 compaction In another study, theophylline:MCC (1:10) pellets were prepared by extrusion/spheronisation using ethanol/water mixture in varying ratio as granulating fluid [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 compressibility This was attributed to the weaker character of the ethanolgranulated 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 compactability 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 the final 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 the fluidized 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 the fluid took place in a very slow manner when drying by oven or desiccation with silica-gel was done 8 S Abdul et al / Journal of Controlled Release 147 (2010) 2–16 This 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, fluidbed dried, oven dried to those pellets dried by desiccation with silicagel 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 their fluid-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 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 multipleunit 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 which film coatings are applied to pellets: modified-release, taste masking, improved stability, elegance, and mechanical integrity can be mentioned as examples Polymers used in the film 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 pseudolatexes) and organic solutions The polymeric particles have to be mechanically deformable to form films under specified conditions This is achieved at a softening temperature [59], which corresponds to a sharp increase in polymer chains mobility [60], hence viscous flow, 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 the film coating created by shrinkage of the film upon solvent evaporation and the differences in the thermal expansion of the coating and the substrate, can produce flaws and cracks in the film 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 extendedrelease and their compression into tablets 3.1.1 Cellulosic polymers Most studies on the compaction of pellets coated with ethylcellulose revealed damage to the coating with a loss of sustained-release properties This is mainly due to the weak mechanical properties of ethylcellulose Ethylcellulose films cast from the plasticized pseudolatexes, 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 values b2% in most cases) Curing of the pseudo-latex-cast ethylcellulose films 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% N 15% N 20% 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 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 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 S Abdul et al / Journal of Controlled Release 147 (2010) 2–16 of 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 densification of the drug/polymer layers upon compaction, 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 more flexible 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 as fillers, and disintegrants were necessary to facilitate faster disintegration of the tablets; the function of these substances were both filling of the interspaces, as well as separation and protection of the coated particles during compression Multiparticulates coated with flexible 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 minimum film-forming temperature of around °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 polymer films The film of Eudragit® NE30D showed high elongation at break of approximately 600% which was flexible 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 of film 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 the film 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 gastric fluid 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 to 50 µm in coated pellets after compression into fast disintegrating tablets The drug release in simulated gastric fluid during h was approximately 20-30% due to broken/cracked film 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® L30D55 film 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 h in simulated gastric fluid 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 above finding 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 highly flexible 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 mixed films 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 the film 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 mixed film 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 10 S Abdul et al / Journal of Controlled Release 147 (2010) 2–16 polymers showing high elasticity combined with sufficient dissolution 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/methylmethacrylate in order to provide more flexible 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: methylmethacrylate (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 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 Debunne et al investigated the influence of formulation and compression parameters on the properties of tablets (tablet mechanical strength, friability and disintegration time) containing entericcoated piroxicam pellets and on the integrity of the enteric coat after compression [78] They studied the influence of three formulation parameters such as amount of coating material (ratio of Eudragit® L30D55/Eudragit® FS30D at different coating levels from 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 continuous 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 incorporated 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 enteric film 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 similar findings 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 hydrochloride 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 ethylcellulose films, 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 minimum film formation temperature The pellets also have a pHindependent drug release and are easily processed [82] Plasticizerfree Kollicoat® SR coatings were too brittle (elongation approximately 1%) and ruptured during compression The flexibility 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 with films 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 polymeric film, 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 ethylcellulose 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 S Abdul et al / Journal of Controlled Release 147 (2010) 2–16 crystals 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 the film 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 of fissures were sintered by exposing the compacted pellets to a temperature above film glass transition temperature, which is about 43 to 44 °C for a film of that composition [89] The compaction of diltiazem hydrochloride pellets coated with ethylcellulose 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 free films 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 in flexible films, which deform and 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 the film 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 in Section 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 11 (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 polymer film to become convoluted and it seemed that the film 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 to fill the void space between the pellets to be compressed and act as cushioning agent to absorb compression forces The filler 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 12 S Abdul et al / Journal of Controlled Release 147 (2010) 2–16 high in all cases Between 30% w/w and 70% w/w pellets per tablet, the influence on the liberation of bisacodyl in 0.1 M HCl after h was in the order: PEG 6000 b Cellactose b Avicel PH 200 b Bekapress D2 Bekapress D2 resulted in the highest damage to the coated pellets as indicated by the fastest drug release because of its fragmentation and high density Avicel and Cellactose are more porous fillers and can therefore absorb higher compression forces Because of the high density of Bekapress D2, a brittle substance, the volume percentage of the pellets was higher when compared with the other excipients This can explain the higher damage of the pellets Bekapress D2 had a true density of 2.63 g/cm3, Cellactose 1.53 g/cm3 and Avicel PH 200 of 1.52 g/cm3 SEM micrographs also revealed the penetration of excipient particles into the coating This, however, did not affect the drug release significantly It was concluded that at lower amount of pellets, single pellets are isolated and surrounded by excipients that act as cushions while at high amount of pellets that are in contact with the punches or with each other, rupture of coated films, occurs as a result of pellet deformation The protective effect of different tableting excipients on the compression of Eudragit® RS coated theophylline granules was studied [95] The order of least damage to the coating was PEG 3350 b MCC b crospovidone b lactose b dicalcium phosphate (Di-tab) The results were in good agreement with the yield pressure of the excipients A combination of 50% MCC, 25% PEG 3350 and 25% crospovidone was most suitable for minimizing the damage to the coating Increasing the compression force mostly resulted in an increase in dissolution rate because of particle crushing However, with PEG 3350 and Di-tab; it resulted in a decrease in dissolution rate because of particle bonding Tablets containing modified-release theophylline pellets with rapid disintegration were prepared by Flament et al [96] The active pellets contained 75% theophylline and 25% inert excipients and were coated with Eudragit® NE30D Tablets compressed from only active pellets were too weak The active pellets were mixed with inert granules which were prepared by wet granulation from MCC, lactose powder and various disintegrants Non-compressed inert granules containing 50% starch resulted in disintegration time of 30 s These granules then facilitated rapid disintegration of tablets in water MCC was used to compensate for the low compressibility of starch and improve the hardness of the tablets produced The optimal formula of inert granules was MCC: corn starch, 1:1 Placebo particles were mixed with Eudragit® NE30D coated diltiazem pellets to evaluate them as cushioning agents during tableting in order to protect the film coat from damage [97] The cushioning properties of α-lactose monohydrate granules, MCC pellets and wax/ starch beads such as paraffinic wax/maltodextrin (WMD) (50:50), paraffinic wax/drum-dried corn starch (DDCS)/ sodium carboxymethyl starch (Explotab) (50:33.3:16.7) were evaluated by comparing the dissolution profile of the coated pellets before and after compression The main compression force was kept constant at 10 kN The deformation mechanism of the material was determined using the Heckel model Mixing α-lactose monohydrate granules with the coated drug pellets (ratio 50:50) did not offer sufficient protection to the film coat since α-lactose monohydrate may have exhibited fragmentation phenomenon rather than deformation during compression When substituting α-lactose monohydrate granules with MCC pellets, a material exhibiting mainly plastic deformation during compression, the controlled release properties from the coated pellets were not maintained at a compression force of 10 kN Whereas MCC pellets are hard, dense spheres [49], the compression behavior of MCC aggregates could be modified by the incorporation of a soft material: glyceryl behenate [28], glyceryl palmitostearate [98], GMS [36,37] and PEG [99] As MCC fibers are able to absorb significant amount of PEG 400 while still yielding soft free-flowing spheres [100], the authors incorporated 15% (w/w) PEG 400 into MCC pellets However, the dissolution profile of the tablets manufactured using this composition showed that cushioning properties of these placebo pellets did not improve In an attempt to protect the film coating during compression, the authors prepared placebo beads based on a mixture of paraffinic wax and WMD (50:50) The authors expected that application of these soft waxy pellets (ratio drug pellets/wax beads: 50:50) would protect the coating during compression and the controlled release properties of the pellets would be maintained However, the drug dissolution rate from these tablets was too low due to the poor disintegration properties of tablet To enhance the disintegration properties of the tablets, these authors used a combination of DDCS (a starch with a large swelling capacity in water, to promote the disintegration of wax beads [101] and Explotab instead of WMS The tablets containing 50% DDCS/Explotab/wax beads had a drug release profile similar to that of uncompressed coated pellets It was concluded that incorporation of soft waxy cushioning beads prevented damage to film-coated diltiazem hydrochloride pellets and the combination of DDCS/Explotab improved the disintegration of tablet containing the same Tablets containing enteric-coated piroxicam pellets were prepared by Debunne et al [102] Drug pellets were prepared by extrusion/ spheronisation process and were enteric-coated with a flexible polymer film consisting of Eudragit® L30D55 and FS30D (ratio 6:4) To protect the enteric-coating during compression, soft placebo wax beads comprising of Paracera P/DDCS/Kollidon CL (50:33.3:16:7) were used as cushioning agents in the ratio of piroxicam pellets, cushioning beads, 60:40 To enhance the tablet disintegration sodium croscarmellose (Ac–Di–Sol), sodium carboxymethyl starch (Explotab) and crospovidone (Kollidon CL) and disintegrant pellets made of Kollidon CL and MCC were added in concentrations up to 10% (w/w) of the tablet mass In addition to flexible coat applied to the pellets, placebo cushioning beads were added to the tablet formulation with the aim of minimizing damage to film coat due to compaction However, such tablets were intact after hr in the disintegration apparatus and they did not disintegrate during the entire dissolution test The addition of disintegrants such as Ac–Di–Sol Explotab, and disintegrant pellets did not improve the disintegration properties of the tablets in 0.1 M HCl, due to the limited swelling properties of Ac–Di–Sol and Explotab and anionic components, in acid media However, 10% (w/w) Kollidon CL powder reduced the disintegration time of these tablets markedly and resulted in tablets with a low friability and hardness of approximately 30 N When tested in 0.1 M HCl, these tablets disintegrated within 15 and released less than 1% of drug within 120 This indicated that the film coat was not damaged during compression The authors concluded that during compaction of enteric-coated pellets with waxy cushioning beads, addition of external disintegrant (Kollidon CL powder, 10%, w/w) results in rapidly disintegrating tablets in 0.1 M HCl with retention of gastroresistant properties of the coated pellets Lundqvist et al investigated factors which could influence the production of modified-release multiparticulate tablets that release the drug-containing pellets and retain a similar dissolution mechanism on tablet disintegration [103] To achieve this, three types of pellets were incorporated in a tablet: 1) pellets containing 80% theophylline as a model drug coated with different thickness of a polymer film coat containing mixture of ethylcellulose and methylcellulose, 2) soft pellets containing GMSas a deformable material, and 3) pellets containing a disintegrant Disintegrant pellets were produced using three different disintegrants such as barium sulfate, iron-oxide, and calcium carbonate Soft pellets were added with the aim to restrict the drug pellets from compression-induced changes and to hold the tablet together by deforming during the compaction Disintegrant pellets were added in order to break the tablet up into pellets when swallowed (or when put in water) The statistical design, fractionated composite design, which included the content of drug pellets, disintegrant pellets, the tableting pressure, the coat thickness, and the type of disintegrants at different level, was employed The S Abdul et al / Journal of Controlled Release 147 (2010) 2–16 mixture with 30% disintegrant pellets, 40% drug pellets, and 30% soft pellets was used as centre point mixture The uncoated pellets released 75% of the theophylline within h The MDT for these pellets was 0.69 h The MDT was 5.55 h and 6.07 h, respectively, for the 4.38% and 8.27% coatings The statistical results showed that these were only small differences in disintegration time between three types of disintegrant pellets The value of the MDT was slightly higher for barium sulfate than for other disintegrants The disintegration time and MDT decreased when the proportion of drug pellets was increased and the proportion of soft pellets was decreased The disintegration time and MDT decreased when the proportion of disintegrant pellets increased and the proportion of soft pellets decreased The disintegration time was not influenced by coat thickness but the dissolution rate decreased with increasing coat thickness When the tableting pressure increased, the value of the MDT and disintegration time increased very slightly At the highest amount of soft pellets, the drug release mechanism was changed, i.e the film around the drug particles was damaged to a larger extent This could be explained by the fact that, during tableting, the soft pellets deformed greatly and the area of contact between these pellets and the drug pellets increased accordingly At the same time the adhesion between the film around the drug pellets and the surfaces of the soft pellets increased During tablet ejection, the generally occurring elastic recovery of the tablet structure led to a peeling effect, i.e parts of the film pulled-off from the surfaces of the drug pellets and adhered to the surfaces of soft pellets The control of drug release by the film was thus damaged A slightly smaller concentration of soft pellets provides an optimal protection of the film and low concentration of the soft pellets lacks protective function during tableting An increase in the amount of disintegrant pellets also altered the dissolution characteristics of the drug from the tablets The possible explanation could be that disintegration occurs due to rupture of the disintegrant pellets instead of separation at the interfaces between the pellets From the range of formulations studied, an optimal formulation should contain about 40% of soft pellets, and the drug pellets should be coated with sufficient film material to give a weight gain of at least 8% 3.5.2 Particle size of excipients To avoid segregation within the pellet-excipient mixture, some authors prefer filler-binders that are almost equal in size to the pellets [35–37,96], while others report of reduced segregation tendency especially when using a small-size MCC [104,105] Wagner et al [79] compacted reservoir pellets (coated with Eudragit® FS30D) using MCC as the excipient, either as a powder or in the form of granules They found the drug release to be less affected when using granules than powder, but recommended use of powder for less flexible polymers In a study by Yao et al [106], excipient particles smaller than 20 µm were found to protect the coating of theophylline particles irrespective of the excipient material used, while larger excipient particles increased the dissolution rate after compaction Yuasa et al [107] compressed microcapsules with mixtures of excipients including MCC of various sizes Small MCC particles increased the dissolution rate less, i.e protected the microcapsules better than larger ones Haslam et al [93], on the other hand, concluded that large excipient particles reduced the compression-effects on coated beads Haubitz et al [105] found that mixtures consisting of 70% w/w theophylline pellets and Avicel PH 101 (X50 = 50 µm) have less tendency to segregate upon tableting than those containing Cellactose (X50 = 200 µm), depending on the shape of the excipient Enteric-coated bisacodyl pellets of mm diameter were compressed into 10 mm tablets using granules and powders as fillerbinders of different particle size and cohesiveness [108] The mixtures contained between 10 and 70% w/w pellets with a particle size in the range 0.8 to 1.25 mm Egermann's equations were used to calculate the coefficient of random variation of content Tablets containing 10% 13 w/w pellets showed pronounced variation in mass and content This was attributed to the large particle size of pellets as compared with the tablet size Mixtures with 30% w/w pellets showed good uniformity of mass and content Segregation occurred if only mixtures of pellets with fine diluent particles were compressed into a tablet which was indicated by high coefficient of variation of content With 50 to 70% w/w pellets in a tablet, good content uniformity was found with all filler-binders used This could be explained by the formation of a percolating cluster of the pellets, which prevented segregation With 50% w/w corresponding to 30% v/v, the coefficient of variation of content agreed well with the values calculated according to Egermann's equation If less than 30% v/v was compressed, suitable granules had to be added until 30% v/v was reached to form a percolating cluster Filler-binder for direct compression like Avicel PH 200 was evaluated as an agent preventing segregation since the particle size of this excipient did not differ too much from that of the coarse components, i.e the pellets or granules The resulting tablets complied well with the requirements for content and mass It can be concluded that 50 to 70% w/w, corresponding to 30% v/v, of pellets in the mixture of coated pellets and filler-binders were necessary to obtain tablets of uniform weight and drug content Tunón et al investigated the influence of size and porosity of excipient on the deformation and densification during compaction and the consequent effect on the drug release from reservoir pellets [109] Drug pellets consisting of salicylic acid and MCC were prepared by extrusion/spheronisation and coated with ethylcellulose Excipient pellets of different size and porosity were prepared Binary mixture of reservoir pellets and the excipient particles were prepared in the proportion 1:7 and lubricated After compaction, the reservoir pellets were retrieved and analyzed The porosity of the drug pellets was similar to the porosity of the high porosity excipient pellets Coating the pellets at 14% weight gain did not produce marked effect on their porosity Drug release from the uncoated drug pellets was rapid; with t50% of Coating prolonged the release considerably, giving a value for t50% of 5.03 h for the uncompacted reservoir pellets SEM showed that the retrieved reservoir pellets were not fragmented but deformed The deformation of the reservoir pellets was strongly dependent on the properties of the excipients, such as size and porosity The tablet containing the small and large size excipient particles produced more irregular shaped reservoir pellets on retrieval Owing to the fact that the excipient pellets were indented into the reservoir pellets, with small indents for the small-size excipients pellets The decreased excipient pellet porosity (corresponding to higher mechanical strength) resulted in more irregular pellets with deeper indents The lower porosity of excipient led to sharper indentations in the reservoir pellets, i.e extended mode I deformation In conjunction with the deformation, the porosity of reservoir pellets was reduced considerably i.e densified Densification of the reservoir pellets was independent of the excipient particles used As observed from SEM, the coating generally seemed to be intact and still adhered tightly to the pellet cores after compaction, although the pellets had been both deformed and densified considerably As far as the effect of the excipients concerned, small high porosity excipient had a limited or a positive effect, i.e prolonged the release time, compared to uncompacted reservoir pellets The most negative effect, i.e the shortest release time, was obtained for the combination of reservoir pellets with large low porosity excipients This could be explained by the hypothesis that the final structure of the coating is the net effect of two parallel processes, one process reducing and one process prolonging the transport time of the drug across the coating The deformation of the substrate pellet may stretch out of the coating, making it thinner or more permeable, which has a negative effect on the control of drug release This would explain the observation that the release rate increased with more irregular compacted reservoir pellets The densification of the substrate pellet may compress the coating, making it thicker or less permeable, and consequently 14 S Abdul et al / Journal of Controlled Release 147 (2010) 2–16 prolong the drug release This may explain the general limited or positive effect of compression It was concluded that the physical characteristics of the pellet core and the protective particles represent potential formulation factors for the compression behavior of reservoir pellets and a controlled drug release rate 3.5.3 Homogeneity and divisibility of tableted pellets dosage form Tableting of pellets into dividable tablets requires a homogenous distribution of pellets within each tablet Variation in machine speed and filler-binders lead to different pellet-distributions in the tablet and therefore has to be considered for each formulation, especially during the scale-up process The influence of five different MCC fillerbinders on the pellet-distribution in tablets was investigated under production-scale conditions [104] Avicel granules were prepared in the size fraction of X50 = 1055, 621 and 194 µm The distribution of Avicel granules in tablets were compared with Avicel PH 101 (X50 = 54 µm) and Vivacel granules (X50 = 179) which were prepared by fluid-bed granulators while Avicel granules were prepared in mixer-granulator Colored coated pellets were tableted along with tableting excipients on instrumented high speed rotary tablet press at four machine speed levels such as 26, 50, 75 and 100 rpm, with compressional force of 20 kN The pellet-distribution on the upper and the lower tablet surfaces was detected via image analysis Tablets produced with coarse granules (X50 = 1055 µm) which were approximately equal in size of the coated pellets showed the most nonhomogeneous pellet distribution A high pellet density was found on the lower surface of the tablet at 26 rpm while the same was found at the upper surface of the tablet at high machine speeds (75 and 100 rpm) This indicated that there was an almost complete vertical segregation of the pellets at higher machine speeds as compared to low speed Smaller but less extensive effects were obtained for tablets containing smaller Avicel granules (X50 = 62 and 194 µm) Among the three Avicel granules, only granules of (X50 = 194 µm) produced tablets with a homogenous pellet distribution at an intermediate machine speed (50 rpm) The authors obtained similar results for Vivacel granules (X50 = 179 µm) as obtained with Avicel granules (X50 = 194 µm) The most homogenous distribution of the pellets, particularly at intermediate and high machine speeds was obtained with Avicel PH 101 (X50 = 54 µm) The authors corrected the segregation tendency of pellets during tableting using different MCC granules with the surface area of respective filler-binders and concluded that Avicel PH 101 (X50 = 54 µm) having a large surface area and a fibrous surface texture built a close percolating infinite clusters that stabilizes the pellets at their location in the mixture against segregation tendency during tableting In the following studies [110], these authors prepared enteric-coated (Eudragit® L30D55 and Eudragit® FS30D) bisacodyl pellets that were compressed into divisible disintegrating tablets at a high speed rotary tablet press and investigated pellet damage via the bisacodyl dissolution during the acid treatment of the drug release test Tablets made with Avicel PH101 as a filler-binder released bisacodyl independent of machine speed between 26 and 75 rpm, while tablets prepared with Avicel granules showed increasing bisacodyl liberation at higher machine speeds This correlated with previous findings With regard to scaleup problems and high production rates, authors selected Avicel PH101 as the most suitable filler-binder for further investigation However, it was not possible to produce tablets containing 70% (w/w) of coated pellets (850 to 1120 rpm) and Avicel PH101 which satisfied the requirement for release of less than 10% bisacodyl within h, not even when the enteric-coating polymer (Eudragit® FS30D) level was raised from 12.5% to 25% with 10% TEC The authors decided to decrease the pellet content in the mixture from 70% (w/w) to 60 % (w/w) in order to prevent damage to coating for same pellet size range Tablets made of 60% (w/w) of pellets and Avicel PH101 as filler-binder released less than 10% bisacodyl within h in simulated gastric fluid at all machine speeds and a compressional force of 20 kN All mixtures containing 70% (w/w) of pellets passed the percolation threshold, thus providing good mass uniformity The true volume of 70% (w/w) of pellets in the mixture was 35% (v/v), the corresponding volume of filler-binder, 14% (v/v), (calculated as Avicel PH101) Consequently, the pellets had a great influence on the properties of the mixture, causing good flow and the mixture remained stable against segregation while being processed into tablets Blends containing 60% (w/w) of pellets at a true volume of 29% (v/v) and a proportion of filler-binder of 18% (v/v) showed less favorable flow properties, due to increased proportion of Avicel PH 101 The addition of 0.3% Aerosil 200 to improve flow properties resulted in tablet of good mass and content uniformity It was concluded that 60 to 70% (w/w) of coated pellet (corresponding to 30% (v/v)) in the mixture and surface area with fibrous texture, like Avicel PH101, enable production of tablets having an approximately homogenous pellet distribution within large range of machine speeds Conclusions The challenges of formulating pellets into tablets are evident The compaction of pellets and mechanical properties of resulting compacts are quite different from those prepared with powdered excipients Various materials and process-related parameters have to be optimized in order to obtain pellet-containing tablets having the same properties, in particular drug release properties The most important variable is the type of polymer selected for the coating of pellets The polymer coat must have the right combination of strength, ductility and thickness to withstand the forces generated during compaction without rupturing Traditionally used polymers for the coating of modified-release dosage from which does not resist the mechanical stresses during compaction, are not suitable for the preparation of multiple unit pellet system The mechanical properties of the polymeric film and its response to stresses of different types must be investigated in order to select the suitable polymer to coat the pellets to be compressed The formulation of pellet core and final tableting excipients has to be carefully selected in order to prevent the rupture of coating Key variables include the pellet–excipient ratio and the compression force The physical characterization of pellet core such as excipients used, size and porosity, type and amount of protective excipients represent potential formulation factors for the compression behavior of pellets-containing tablets On reviewing the literature on compressed beads, it is evident that the compaction of matrix-type pellets demonstrates fewer problems than reservoir-type pellets However, proper selection of polymers to withstand the mechanical stresses of compaction and suitable choice 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[40] A Tunon, G Alderborn, Granule deformation and densification during compression of binary mixture of granules, Int J Pharm 222 (2001) 65–76 [41] M.R Abbaspour, F Sadeghi, H .A Garekani, Thermal treating as a tool to produce plastic pellets based on Eudragit RS PO and RL PO aimed for tableting, Eur J Pharm Biopharm 67 (2007) 260–267 [42] M.R Abbaspour, F Sadeghi, H .A Garekani, Preparation and characterization... characterization of ibuprofen pellets based on Eudragit RSPO and RLPO or their combination, Int J Pharm 303 (2005) 88–94 [43] S Azarmi, J Farid, A Nakhodchi, S.M Bahari-saravi, H Valizadeh, Thermal treating as a tool for sustained release of indomethacin from Eudragit RS and RL matrices, Int J Pharm 246 (2002) 171–177 [44] N Billa, K Yuen, K Peh, Diclofenac release from Eudragit contain matrices and of thermal... properties of tablet To enhance the disintegration properties of the tablets, these authors used a combination of DDCS (a starch with a large swelling capacity in water, to promote the disintegration of wax beads [101] and Explotab instead of WMS The tablets containing 50% DDCS/Explotab/wax beads had a drug release profile similar to that of uncompressed coated pellets It was concluded that incorporation of... drug release mechanism was changed, i.e the film around the drug particles was damaged to a larger extent This could be explained by the fact that, during tableting, the soft pellets deformed greatly and the area of contact between these pellets and the drug pellets increased accordingly At the same time the adhesion between the film around the drug pellets and the surfaces of the soft pellets increased... Eudragit® FS30D) bisacodyl pellets that were compressed into divisible disintegrating tablets at a high speed rotary tablet press and investigated pellet damage via the bisacodyl dissolution during the acid treatment of the drug release test Tablets made with Avicel PH101 as a filler-binder released bisacodyl independent of machine speed between 26 and 75 rpm, while tablets prepared with Avicel granules... (Ed.), Multiparticulate Oral Drug Delivery, Marcel Dekker, New York, 1994, pp 181–215 S Abdul et al / Journal of Controlled Release 147 (2010) 2–16 [8] M Marvola, M Rajamiemi, E Marttila, K Vahervno, A Sothmann, Effect of dosage form and formulation factors on the adherence of drugs to esophagus, J Pharm Sci 72 (1983) 1034–1037 [9] J.W Conine, H.R Hadley, Preparation of solid pharmaceutical spheres,... physical characteristics of the pellet core and the protective particles represent potential formulation factors for the compression behavior of reservoir pellets and a controlled drug release rate 3.5.3 Homogeneity and divisibility of tableted pellets dosage form Tableting of pellets into dividable tablets requires a homogenous distribution of pellets within each tablet Variation in machine speed and filler-binders... film coat from damage [97] The cushioning properties of α-lactose monohydrate granules, MCC pellets and wax/ starch beads such as paraffinic wax/maltodextrin (WMD) (50:50), paraffinic wax/drum-dried corn starch (DDCS)/ sodium carboxymethyl starch (Explotab) (50:33.3:16.7) were evaluated by comparing the dissolution profile of the coated pellets before and after compression The main compression force was kept... 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