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A mechanistic investigation on the utilization of lactose as a protective agent for multi-unit pellet systems
Pharmaceutical Development and Technology
Abstract
Abstract The effect of lactose particle size on the extent of pellet coat damage was investigated. The extent of pellet coat damage increased linearly with lactose median particle size. It was observed that coated pellets compressed with coarser lactose grades had larger and deeper surface indentations. The surfaces of the pellets compressed with coarser lactose grades were also found to be significantly rougher. Micronized lactose was capable of protecting pellet coats from damage brought about by the presence of coarser lactose particles. The findings suggested a protective effect that micronized lactose conferred to pellet coats was not only through dimensional delimitations but also by higher interparticulate friction and longer particle rearrangement phase. As a result, the pellet volume fraction in the system was reduced. The extent of pellet coat damage was found to escalate when the pellet volume fraction in such system increased beyond a critical value of 0.39.
... At least three replicates were carried out and the results were averaged. The true volume V p of pellets was calculated as reported previously [5,40,43] A compaction simulator (Styl'One Evolution, Medelpharm, Beynost, France) was used to fabricate the MUPS tablets. From the compaction profile, using the control and data-capture software (Analis, Version 2.08.5, Medelpharm, Beynost, France), different energetic parameters were derived as described in previous studies [44][45][46]. ...
... where r and h are the MUPS tablet radius and height, respectively. The MUPS tablet pellet volume fraction was calculated as reported previously [5,40] using the following equation: ...
... The K values of the MCC pellets were generally higher than those of the XPVP pellets. A previous study evaluated the effects of increasing the pellet volume fraction and a critical pellet volume fraction of 39% was identified [40]. Below this critical pellet volume fraction, pellets were postulated to form a percolating, simple cubic lattice network that permitted increases in pellet volume fraction without much increase in coat damage. ...
Multi-unit pellet system (MUPS) tablets were fabricated by compacting drug-loaded pellets of either crospovidone or microcrystalline cellulose core. These pellets were produced by extrusion-spheronization and coated with ethylcellulose (EC) for a sustained drug release function. Coat damage due to the MUPS tableting process could undermine the sustained release function of the EC-coated pellets. Deformability of the pellet core is a factor that can impact the extent of pellet coat damage. Thus, this study was designed to evaluate the relative performance of drug-loaded pellets prepared with either microcrystalline cellulose (MCC) or crospovidone (XPVP) as a spheronization aid and were comparatively evaluated for their ability to withstand EC pellet coat damage when compacted. These pellets were tableted at various compaction pressures and pellet volume fractions. The extent of pellet coat damage was assessed by the change in drug release after compaction. The findings from this study demonstrated that pellets spheronized with XPVP had slightly less favorable physical properties and experienced comparatively more pellet coat damage than the pellets with MCC. However, MUPS tablets of reasonable quality could successfully be produced from pellets with XPVP, albeit their performance did not match that of vastly mechanically stronger pellets with MCC at higher compaction pressure.
... The challenges presented in designing MUPS tablets require substantial research work at understanding how cushioning fillers can mitigate compaction-induced pellet coat damage and the conditions which may potentially aggravate or ameliorate the extent of damage. In studies using lactose, the particle size of the lactose was a critical attribute and micronized lactose was reported to be best [4,5]. Highly compressible excipients were also found to be good cushioning fillers [6][7][8][9]. ...
... The volumetric ratio between the filler and pellets or, critical pellet volume fraction [14] was reported to influence the extent of pellet coat damage. Critical pellet volume fraction values ranging from 0.374 [14] to 0.39 [4] were optimal to maintain a percolating network of cushioning fillers around the pellets, thereby minimizing pellet-pellet contacts during compression. In addition, the ratio between cushioning filler and pellets was also found to influence mechanical strength, friability and disintegration time of the resultant tablets [15]. ...
Damage to the drug diffusion coat barrier of controlled release pellets by the compaction force when preparing multiple-unit pellet system tablets is a major concern. Previous studies have shown that pellets located at the tablet axial and radial peripheral surfaces were more susceptible to damage when compacted due to the considerable shear encountered at these locations. Hence, this study was designed to assess with precision the impact of pellet spatial position in the compact on the extent of coat damage by the compaction force via a single pellet in minitablet (SPIM) system. Microcrystalline cellulose (MCC) pellet cores were consecutively coated with a drug layer followed by a sustained-release layer. Chlorpheniramine maleate was the model drug used. Using a compaction simulator, the coated pellets were compacted singly into 3 mm diameter SPIMs with MCC as the filler. SPIMs with individual pellets placed in seven positions were prepared. The uncompacted and compacted coated pellets, as SPIMs, were subjected to drug release testing. The dissolution results showed that pellets placed at the top-radial position were the most susceptible to coat damage by the compaction force, while pellets positioned within the minitablet at the middle and upper quadrant positions showed the least damage. The SPIM system was found to be effective at defining the extent of coat damage to the pellet spatial position in the compact. This study confirmed that coated pellets located at the periphery were more susceptible to damage by compaction, with pellets located at the top-radial position showing the greatest extent of coat damage. However, if the pellet was completely encrusted by the cushioning filler, coat damage could be mitigated. Further investigations were directed at how the extent of coat damage impacted drug release. Interestingly, small punctures were found to be most detrimental to drug release whilst coats with large surface cuts did not completely fail. A damaged pellet coat has some self-sealing ability and failure is not total. Thus, this study provides a deeper understanding of the consequence of coat damage to drug release when sustained release coated pellets are breached.
... Micronized lactose (ML) had a cushioning effect during the tableting of multiparticulates and the degree of coating damage increased linearly with the increasing of its median particle size (83,84). It was observed that ML could more effectively protect pellet coats from damage than coarser lactose grades that caused deeper and larger surface indentation on the coating film during compaction. ...
... It was observed that ML could more effectively protect pellet coats from damage than coarser lactose grades that caused deeper and larger surface indentation on the coating film during compaction. Moreover, the protective effect conferred by ML was believed to be not only through dimensional delimitations, but also by higher interparticulate friction and longer particle rearrangement phase (83). Although spray drying of ML led to slight reduction in the cushioning effect, this processing method significantly improved its physicomechanical properties. ...
Particle engineering has become a hot topic in the field of modified-release delivery systems during last decades. It has a wide range of pharmaceutical applications and is a bridge linking between drugs and drug delivery systems. Particles are an important part of many dosage forms and viewed as a carrier of drugs. Their size, shape, crystalline form, and structure directly affect the stability and releasing pattern of drugs. Engineering size or modifying particles by forming porous, core-shell, or skeleton structures can realize the development and utilization of functionally modified release systems (including fast-release systems, sustained-release systems, and targeted-release systems). However, there are certain problems in the practical application, such as bitter taste and coating damage. Combining with some polymer or lipid materials to form core-shell or embedded structures is considered as the key to taste masking. And, using cushioning agents is proven to be effective in preserving the integrity of the functional coating film of multiparticulates during tableting. To sum up, this review, from a particle engineering point, expounds the influence of different factors on the functionality of particles and offers some useful comments and suggestions for industry personnel.
... Small particles pack well and leaves less peaks and valleys. Hence, the smaller the particles size the smoother is the surface of the pellets [20,21]. Starting materials, such as Microcrystalline cellulose (MCC) gives pellets with smoother surfaces than those produced by crosspovidone or lactose. ...
The aim of this work was to identify and collate the major common challenges that arise during pellet development. These challenges focus on aspects right from raw material properties until the final drying process of the pelletization. The challenges associated with the particle size of drug and excipients, physicochemical properties, drug excipient interaction and the effect of type/grade and amount of raw material on the pellet properties are covered in this review. Technological and process related challenges within the commonly used pelletization techniques such as extrusion-spheronization, hot-melt extrusion and layering techniques are also emphasized. The paper likewise gives an insight to the possible ways of addressing the quality of pellets during development.
... A recent study conducted by Chin, Chan, and Heng suggested that the particle size of the lactose as a cushioning layer influenced the integrity of the compressed pellets. Pellets compressed with coarse lactose particles had deeper and larger indentation, whilst micronized lactose managed to protect the pellets from damage [49]. ...
Oral modified-release multiparticulate dosage forms, which are also referred to as oral multiple-unit particulate systems, are becoming increasingly popular for oral drug delivery applications. The compaction of polymer-coated multiparticulates into tablets to produce a sustained-release dosage form is preferred over hard gelatin capsules. Moreover, multiparticulate tablets are a promising solution to chronic conditions, patients’ adherence, and swallowing difficulties if incorporated into orodispersible matrices. Nonetheless, the compaction of multiparticulates often damages the functional polymer coat, which results in a rapid release of the drug substance and the subsequent loss of sustained-release properties. This review brings to the forefront key formulation variables that are likely to influence the compaction of coated multiparticulates into sustained-release tablets. It focusses on the tabletting of coated drug-loaded pellets, microparticles, and nanoparticles with a designated section on each. Furthermore, it explores the various approaches that are used to evaluate the compaction behaviour of particulate systems.
... Also importantly, micronized lactose does not fragment into sharp-edged fragments when compacted with EC-coated pellets. Moreover, micronized lactose was postulated to adhere to the surfaces of coated pellets, which helped to dissipate compression stress by a lubricative effect on the coated pellets [64]. It was observed that smaller lactose particles could more effectively protect the coating film from compression damage, an effect attributed to the more effective transmission of stress because of the larger number of points of contact [65]. ...
The tablet of multi-unit pellet system (TMUPS), using coated pellets, for controlled release of drugs is an effective therapeutic alternative to conventional immediate-release dosage forms. The main advantages of TMUPS include a) ease of swallowing and b) divisible without compromising the drug release characteristics of the individual units. TMUPS can be prepared more economically than pellet-filled capsules because of the much higher production rate of tableting process. In spite of the superiorities of TMUPS, its adoption has been challenged by manufacturing problems, such as compromised integrity of coated pellets and poor content uniformity. Herein, we provide an updated review on research, from both scientific literatures and patents, related to the compaction of TMUPS. Factors important for the successful production of TMUPS are summarized, including model drug property, potential cushioning agents, and novel techniques to protect pellets from damage. This review is intended to facilitate the future development of manufacturable TMUPS with drug release behavior similar to that of the original coated pellets.
... It is also necessary to examine the impact of compacting coated particles with commonly used excipients, often necessitate the design of sacrificial granules to mitigate the harsh conditions required for the formation of compacts in a die of the tablet press [3,4]. Excipients with smaller mean particle size could reduce the coat damage of multi-particulates during compression [5]. However, even with the usage of the finest grade of lactose, the drug release was about 3 times faster than the uncompressed coated particles. ...
Pellet coat damage in multi-unit pellet system (MUPS) tablets has previously been studied and addressed with limited success. The effects of lactose filler material attributes on pellet coat damage have been relatively well-studied but a similar understanding of microcrystalline cellulose (MCC) is lacking notwithstanding its high cushioning potential. Hence, the relationships between MCC attributes and pellet coat damage were investigated. Single pellet in minitablets (SPIMs) were used to isolate pellet-filler effects and reveal the under-unexplored impact of risk factors found in MUPS tablets. MUPS tablets and SPIMs were prepared with various grades of MCC and pellets with an ethylcellulose or acrylic coat at various compaction pressures. Subsequently, the extent of pellet coat damage was determined by dissolution test and quantified using two indicators to differentiate the nature of the damage. A multi-faceted analytical approach incorporated linear regression, correlations and a classification and regression tree algorithm and evaluated how MCC attributes, such as flowability, particle size and plastic deformability, exert various influences on the extent of ethylcellulose and acrylic pellet coat damage. This analysis improved the understanding of the different mechanisms by which pellet coat damage to these two polymer types occurs which can help enhance future pellet coat damage mitigation strategies.
Lactose is one of the most widespread excipients used in the pharmaceutical industry. Because of its water solubility and acceptable flowability, lactose is generally added into tablet formulation to improve wettability and undesirable flowability. Based on quality by design, a better understanding of the critical material attributes (CMAs) of raw materials is beneficial in guiding the improvement of tablet quality and the development of lactose. Additionally, the modifications and co-processing of lactose can introduce more-desirable characteristics to the resulting particles. This review focuses on the functionality, CMAs, applications, modifications and co-processing of lactose in tablets.
Compaction of multiple-unit pellet system (MUPS) tablets has been extensively reported to be potentially challenging. Thus, there is a need for non-segregating cushioning agents to mitigate the deleterious effect of the compaction forces. This study was designed to investigate the use of porous pellets as cushioning agents using different drying techniques to prepare pellets of various porosities and of different formulations. The pellets fabricated were characterized for their porosity and crushing strength. Subsequently, MUPS tablets were prepared using blends of polymer-coated pellets and custom-designed cushioning pellets by compacting at different pressures. The effects of pellet volume fraction and dwell time on the pellet coat damage, as well as the tensile strength of the resultant MUPS tablets were also investigated. Compacts with coated pellet volume fraction of 0.21 exhibited the best cushioning effect when tableted at different compression speeds with both gravity and force feeders. The findings from this study showed that cushioning pellet porosity was highest when drying was carried out by freeze drying, followed by fluid bed drying and oven drying. There was an inverse relationship between cushioning pellet porosity and strength. The tensile strength of tablets prepared from freeze dried pellets was highest. The protective effect of the cushioning pellets was principally dependent on their porosity. Also, pellet volume fraction in the compacts and compaction pressure used had remarkable effect on pellet coat damage. When unprocessed powders were compacted by automatic die filling, capping and lamination problems were observed. However, tablets of reasonable quality were made with the cushioning pellets. Freeze dried pellets containing crospovidone were found to be promising as cushioning agents and had enabled the production of MUPS tablets even at higher compaction pressures, beyond the intrinsic crushing strength of the coated pellets.
This article summarizes the critical factors involved in product development of a single dosage form formulated by compacting ethyl cellulose (EC) coated controlled release pellets into a tablet. The greatest challenge associated with this type of complex system is to minimize the effect of compression on the drug release. The effects of compression on the drug release were optimized with combination of the following factors (1) particle size of the core pellets, (2) the selection of the coating polymer’s viscosity grade, and (3) emergence of cushioning agents. The optimization of these factors provided superior protection for the controlled release coated pellets; therefore, the desired drug release from the tablet was successfully achieved as designed. However, the drug release rates from the coated pellets before and after the compression were minimized and exhibited only a slight difference.
Ultra-fine particle processing system (UPPS) was more advantageous in producing microparticles (MPs) than the conventional technologies since it was applicable for a wide range of drugs and the MPs could be manufactured in a successive and controllable way under mild conditions. The MPs based on this technology showed small uniform particle size, proper surface roughness, and dense structure, which were anticipated to benefit tablet compaction. Therefore, ethyl cellulose (EC) was selected as the matrix material to confirm the superiorities of UPPS produced MPs for compaction due to its rigidity and inflexibility. To improve the encapsulation efficiency (EE%) of EC based MPs, hydrophilic/hydrophobic plasticizers and polymers were added, and the effect was mechanistically investigated regarding to the polymer properties and particle size of MPs. The results revealed that the EE% of MPs was significantly improved in the presence of hydrophilic polymers, which was mainly related to the reduced drug leakage as a result of modified polymer properties and decreased particle size of MPs. The forming mechanism of MPs determined by X-ray photoelectron spectroscopy (XPS) revealed that the MPs were enriched with low molecular weight polymers on the surface due to the unevenly migration driven by the centrifugal force. The topography of MPs determined by atomic force microscopy showed that the MPs had considerable rough surface to the commercial excipient, which benefited for further compaction. Consequently, the dissolution profile of MPs after compaction was approachable to that of original MPs and the tablets showed optimal content uniformity.
Compaction of multiple-unit pellet system (MUPS) tablets has been extensively studied in the past few decades but with marginal success. This study aims to investigate the formulation and process strategies for minimizing pellet coat damage caused by compaction and elucidate the mechanism of damage sustained during the preparation of MUPS tablets in a rotary tablet press. Blends containing ethylcellulose-coated pellets and cushioning agent (spray dried aggregates of micronized lactose and mannitol), were compacted into MUPS tablets in a rotary tablet press. The effects of compaction pressure and dwell time on the physicomechanical properties of resultant MUPS tablets and extent of pellet coat damage were systematically examined. The coated pellets from various locations at the axial and radial peripheral surfaces and core of the MUPS tablets were excavated and assessed for their coat damage individually. Interestingly, for a MUPS tablet formulation which consolidates by plastic deformation, the tablet mechanical strength could be enhanced without exacerbating pellet coat damage by extending the dwell time in the compaction cycle during rotary tableting. However, the increase in compaction pressure led to faster drug release rate. The location of the coated pellets in the MUPS tablet also contributed to the extent of their coat damage, possibly due to uneven force distribution within the compact. To ensure viability of pellet coat integrity, the formation of a continuous percolating network of cushioning agent is critical and the applied compaction pressure should be less than the pellet crushing strength.
The main aim of the present study was to compare the transit through the entire gastro-intestinal channel of a membrane-coated, multiple-unit system containing metoprolol and a single-unit placebo tablet using gamma-scintigraphy. The two formulations were simultaneously administered, together with a breakfast (2800 kJ), to eight healthy male volunteers. The mean gastric emptying time for the pellets was 3.6 (range 1.5–5.0) h on average and the mean gastric emptying time for the tablet was 9.6 (range 3.3-(14–24)) h. This difference was statistically significant. The mean transit through the small intestine, 3.1 (range 1.5–5.7) h and 2.0 (range 1.0–3.3) h for the pellets and the tablet respectively, did not differ significantly between the formulations. The pellets had a longer residence time in the colon in all subjects compared with the tablet. The mean colon transit time was 28 (range 6.0–48) h on average for the pellets and 15 (range 3.8–26) h for the tablet. The tablet was expelled 26 (range 9.5–42) h after intake on average, whereas the pellets remained for a significantly longer time period (mean 35, range 10–55 h). The desired extended-release properties and metoprolol absorption was obtained throughout the entire gastrointestinal (GI) tract.
To compress coated particles into tablets without mechanical damage to the coating membrane during compression, the effect of the particle size of various pharmaceutical additives was investigated by comparing the dissolution rate and the membrane integrity of ethylcellulose coated theophylline powder. Results showed that smaller additive particle size was superior in protecting the membrane from damage, and thus additive particle size might be one of the most omportant factors affecting the dissolution characteristics of compressed tablets containing coated particles. Twenty μm seemed to be the critical particle size for each kind of additive to obtain good protective effect. Up to this size, all additives played the role of cushioning and the coating membrane was almost perfectly protected from potential damage by the compression force.
Controlled release enalapril millispheres of different diameters were prepared and tableted with excipients in a 1:1 ratio on a Carver press. Drug release rate profiles showed that the microporous coating on the millispheres was severely damaged during the compression process. Overcoating of the microporous coating with hydroxypropyl methylcellulose E5 (HPMC E5) protects the microporous coating during compression by absorbing and dissipating the compressional forces. This protection becomes more pronounced as the size of the millispheres is reduced. A novel investigation of individual millisphere strength was conducted to identify the most favorable coating and size combination which would preserve the controlled release properties of the millispheres.
Binary mixtures of different particle size fractions of α-lactose monohydrate were compacted into tablets. The results showed decreased crushing strengths and decreased internal specific surface areas of the tablets as compared with the values calculated by linear interpolation of the data obtained for the corresponding single powder fractions. The extent of decreased strength and decreased surface area of the tablets was found to depend upon the weight ratio of the finer sieve fraction in the blend and to increase with the diameter ratio between coarse and finer particles. These results indicate an interaction with respect to consolidation and compaction which is explained by decreased fragmentation potentials, caused by increased packing densities of the binary mixtures of different particle size fractions of crystalline lactose. All data on crushing strength and internal specific surface area of the tablets fitted the unique linear relationship between these parameters, as found previously for tablets compressed from binary mixtures of equal particle size fractions of different types of crystalline lactose.
Multiparticulates are discrete particles that make up a multiple-unit system. They provide many advantages over single-unit systems because of their small size. Studies have shown that multiparticulates are less dependent on gastric emptying, resulting in less inter- and intra-subject variability in gastrointestinal transit time. They are also better distributed and less likely to cause local irritation. The drug dose in a multiple-unit system is divided over the multiparticulates that make up that system. As such, failure of a few units may not be as consequential as failure of a single-unit system.
Multiparticulates may be prepared by several methods. Different methods require different processing conditions and produce multiparticulates of distinct qualities. Some of these methods may be broadly classified as pelletization, granulation, spray drying, and spray congealing. Drug particles may be entrapped within the multiparticulates or layered around them. Subsequently, these multiparticulates may be modified in many ways to achieve the desired drug-release profile.
One approach to the modification of drug-release profiles in multiparticulates is to coat them. Reasons for the application of coating onto multiparticulates are to obtain functional coats, provide chemical stability, improve physical characteristics, and enhance patient acceptance. Coats are formed from various polymeric coating materials broadly classified as aqueous polymer dispersions, polymer solutions, molten polymers, and dry powders. Depending on the type of coating material used, functions such as sustained release (SR), targeted release, delayed release, and pulsatile release can be achieved. The focus of this review is on SR coating.
The most common method used for the application of coating onto multiparticulates is air suspension coating. Other methods include compression coating, solvent evaporation, coacervation, and interfacial complexation. It is also possible to form coated microparticles by spray drying and spray congealing.
A major part of this review is focused on factors affecting the coating of multiparticulates and drug-release characteristics from SR coated multiparticulates. Knowledge of these factors is important in the development of SR coated multiparticulates because control of these factors ensures consistency of drug release between batches of multiparticulates. These factors may be classified into four groups: characteristics of cores, characteristics of SR coats, coating equipment, and coating process conditions.
Abstract The factors affecting the tabletability of formulations containing uncoated and/or coated microspheres were discussed by presenting a case study. The size and shape, as well as surface properties of microspherical particles, the type and amount of coating agent, selection of the external additives, and the rate and magnitude of the pressure applied were found to be the most critical factors to be considered in order to obtain and maintain the desired drug release properties of the microspheres. It was found that microcrystalline cellulose was needed in order to produce satisfactory beads in terms of size, shape and surface characteristics. The microsphere formulations, which were found to be highly sensitive to lubrication, were more compressible than their powder forms, but produced much weaker tablets. When coated with Surelease, increasing the amount of coating on the pellets reduced the tensile strength of their compacts. Compaction of the microspheres at high velocities resulted in a decrease in the tensile strength values and an increase in the volumetric strain recovery values. Dissoultion studies revealed that, regardless of the amount of coating applied, the coated microspheres lost their sustained release properties during compaction.
Compaction characteristics of Surelease coated pellets were studied using several techniques including porosity change, Heckel equation, total work of compaction and elastic recovery indices. The reduction in yield strength and an increase in tensile strength of the compacts caused by the addition of a Surelease coating to the pellets is ascribed to the interlocking forces between the substrate and the coating and to the development of additional bonds formed by plastic deformation of the coating during compaction. However, increasing amounts of the coating on the pellets reduced their yield strengths and resulted in compacts with lower tensile strength and higher elastic recovery values. The effect of the rate of load application on the compaction characteristics of Surelease coated pellets was also studied. As the punch velocity increased there was a reduction in the tensile strength values of the compacts and an increase in both yield pressure and elastic recovery values. The change in the magnitude of these values with the rate of load application was greater for the compacts made from pellets coated with increasing amounts of Surelease. A nonlinear optimization technique was also employed to further investigate the effect of rate of load application on the coated pellets. Pellets coated with increasing amounts of coating exhibited relatively more punch velocity dependence. Dissolution studies revealed that coated pellets lost their sustained release characteristics on compaction due to formation of cracks within the coating and to the fragmentary/elastic nature of the pellets.
In this article, the effect of original particle size on the Kawakita parameters, denoted a and b, has been studied using four model materials of different compression mechanics. It was found that fine powders, possibly showing significant particle rearrangement at low compression pressures, showed low values of parameter b(-1) and high values of parameter a. It is thus proposed that the product of these parameters is an indication of the overall contribution of particle rearrangement to the compression profile. Above a critical original particle size of a powder, particle rearrangement is negligible for the overall compression profile and below this critical particle size, particle rearrangement becomes significant. A critical particle size of about 40 microm was obtained. A classification of powders into groups dependent on the incidence of particle rearrangement is discussed and it is suggested that a rearrangement index and a classification system could be used as tools to enable rational interpretations of global compression parameters.
Compression data from different size fractions of lactose, chloroquine diphosphate, stearic acid and calcium carbonate have been analysed using the Walker and the Heckel compression equations. Points of inflection in graphs of log applied pressure vs the reciprocal of the packing fraction at low pressures corresponded closely to figures for theoretical packing conditions for equisized spheres and are attributed to a change in the stage of compression. The degree of particle slippage and rearrangement taking place during compression has been shown to increase as the particle size of the powder decreases and to be more extensive for powders composed of non-spherical particles. In addition, three types of compression behaviour have been distinguished for the four powders studied.
The effect of punch velocity over the range 0.033-300 mm s-1 on the compaction properties of lactose, microcrystalline cellulose and a drug substance (a phthalazine derivative) for a range of particle sizes has been studied using the yield pressure derived from the Heckel relationship and a strain rate sensitivity index (SRS index), as the criteria to describe their behaviour. For lactose, a material which deforms by a mixed mechanism of particle fracture and plastic deformation at the contact points, the yield pressure increased and the SRS index decreased as particle size decreased, due to a reduction in the amount of fragmentation of the particles. For microcrystalline cellulose, a material which is known to deform plastically, the yield pressure and the SRS index were independent of particle size. For the phthalazine derivative the yield pressure increased as particle size decreased; however the SRS index reduced from 41% to zero, indicating that the deformation mechanism was changing from plastic flow to brittle behaviour. This decrease in the SRS index has been explained in terms of the relative amounts of strain-hardened material produced as milling severity increased, resulting in an increasing resistance to deformation and thus an apparent increase in brittle behaviour as particle size decreased.
Tablets were prepared from three particle-size fractions of crystalline and spray-dried lactose by the application of known pressures at a slow speed (upper punch speed 1 mm./min.) and a high speed (upper punch speed 600 mm./min.). The relative volumes and densities of the tablets were determined after ejection from the die and, for the slow speed, under pressure. Changes in volume with load were dependent on the particle size, on the speed of compaction, and on whether the volume was determined at pressure or after release of pressure. Calculation of the mechanism of densification by two different methods showed that particle rearrangement was greatest for the smallest size fraction both at slow and high speeds. Calculation of the yield pressure and the pressure necessary to fill the interparticle void space also was made.
Elucidate the compactibility of binary mixes from their organization as compared to the traditional approach involving the different behavior of the materials under compression (plastic or brittle).
Several materials were selected from their surface energies. Binary mixes 50/50 v/v were prepared from different sieved or freeze-milled fractions. The tensile strengths of the tablets obtained at two compression forces were compared with those of series of compacted binary mixes containing different proportions of the raw materials (concept of equivalent media).
In the case of interacting mixes, when the differences in particle size between the fractions blended increased, the material with the lowest particle size coated the largest particles more efficiently. Consequently, the tensile strengths of the tablets obtained became closer to the tensile strengths obtained from the pure coating material. For the non-interacting systems, the experimental tensile strengths were very close to the values calculated from the tensile strengths of the pure materials.
This study clearly demonstrates the influence of the organization of binary mixes on their compactibility. The adhering material makes a percolating network governing the tensile strength of the tablet. From an industrial point of view, it is possible to improve the compactibility of binary mixes without changing their composition by selecting the appropriate organization.
Two different types of pellets, i.e. drug-free sugar spheres, and pellets, spray-layered with crystalline theophylline and coated with Eudragit RS/RL, were tabletted each in combination with matrix-forming powder mixtures of Avicel PH200 and PEG 4000. The die fills from pellets and powder mixtures were regarded as two-compartment systems with a volume fraction of the pellets being limited to 0.52 corresponding to a cubic lattice, and the maximum degrees of densifications were adjusted related to the matrix. To data measured during single compression cycles on an instrumented eccentric tabletting machine and transformed appropriately, the Kawakita equation, the Heckel function, and a modified Weibull function were fitted, and the total work of compression was calculated. The Kawakita model fitted well systems with both types of pellets. Its parameters reflected the additional densification of the theophylline pellets separately from that of the matrix formers. The Heckel function could only be applied to systems containing non-porous sugar spheres, since the theophylline pellets underwent considerable densification and deformation. Only, when the Heckel porosity function was related to the volume fraction of the matrix, excluding the sugar spheres, the approximately linear regions for mixtures with increasing volume proportions of sugar spheres occured in comparable regions of densification. Parameters of the modified Weibull function demonstrated an increasing resistance against densification with increasing amounts of pellets. The total work of compression increased steeply with increasing volume fractions for pellets from 0.42 to 0.46 indicating, that the resistance against densification already rose when the pellets were still isolated. In conclusion, the combination of dynamic and kinetic models provides a comprehensible insight into the process of tabletting powder mixtures with pellets. Particularly, the Kawakita model was a suitable tool to differentiate the actual changes in porosity during compression from the compressibility of such complex systems.
Three pharmaceutical excipients (microcrystalline cellulose, lactose, anhydrous calcium phosphate) and their binary mixtures were compacted to form compacts of various mean porosities. Some mechanical properties (Young's modulus, tensile strength and Brinell hardness) were studied on these compacts. The mechanical properties of the binary mixtures were not proportional to the mixture composition expressed in mass. More, for all the properties, a negative deviation was always observed from this linear relationship. In reference to a composition percolation phenomenon, critical mass fractions were detected from the graph mechanical property vs. mass composition of a mixture. The results obtained with Brinell hardness differed from the results of the Young's modulus and the tensile strength, i.e. the most plastic material in the binary mixture controlled the mixture behaviour. Secondly, a predictive model based on a statistical approach was proposed for the Young's modulus and the tensile strength. The validity of this model was verified on experimental data, and an interaction parameter used to characterize the affinity of the two compounds was calculated. Finally, the X-ray tomography technique was applied to the compacts of cellulose/phosphate mixtures to obtain cross-sections images of the compacts. The analysis of the cross-sections images allowed explaining the no linear relationship of the different mechanical properties results observed on these binary mixtures.
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