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Preparation of co-spray dried cushioning agent containing stearic acid for protecting pellet coatings when compressed
Drug Development and Industrial Pharmacy
Abstract
This study investigated the applicability of stearic acid as a co-adjuvant in cushioning agent formulated to prevent coat damage when compressing coated pellets. The co-processed and physical blended fillers were prepared by spray drying and physically blending, respectively, with filler ingredients consisting of stearic acid, microcrystalline cellulose, fully gelatinized starch, and corn starch. Pellets containing drug were produced by coating onto non-pariels a drug layer of metformin followed by a sustained-release layer. Drug release from tablets composed of co-processed or physical blended fillers (0, 1, 5, and 10% stearic acid levels) and coated drug containing pellets were analyzed using similarity factor F2. Under the same force and the stearic acid level, co-processed fillers produced pellet containing tablets which showed higher F2 or t50 values and tensile strengths as well as lower yield pressures as compared with tablets containing physical blended fillers. It was shown that the destructive degree of pellet coating was significantly reduced after being co-processed by homogenization and the incorporation of stearic acid in the cushioning agents, as shown by the improved F2 and t50 values. In addition, disintegrate times of tablets containing co-processed agents decreased despite the hydrophobic stearic acid. In conclusion, the inclusion of stearic acid in co-processed cushioning agents was effective at protecting compacted coated pellets from compression-induced damage without compromising disintegratability. The findings could serve as a step towards resolving the technical challenges of balancing the drug release profiles, tablet tensile strength, and disintegration time of compacting coated pellets into multi-particulate-sustained release tablets.
... The development of co-processed excipients consisting of MCC, gelatinised starch and stearic acid for pellet cushions has been carried out by Li et al. to produce tablets containing multi-particulate sustainedrelease metformin HCl pellets. The result showed that co-processed excipients effectively protected pellets during compression without compromising their disintegrability compared to physical blend cushioning agents at the same composition [71]. [77,78]. ...
The formulation of drug dosage forms is hindered by the scarcity of ideal single-component excipients essential for achieving excellent performance. This necessity requires modification of excipients to improve its functionality and applicability, thereby supporting the manufacturing of dosage forms. One of the effective strategies to develop the excipient is through co-processing two or more excipients, which is classified as physical modification to improve excipients functionality properties with complex interaction that does not occur at simple physical mixture. The physical interaction between those excipients occurs at the sub-particle level, promoting the alteration of bulk properties without significant chemical changes. Co-processed excipients result in superior or multifunctional qualities that provide advantages in drug development phase proven by recent scientific studies. Therefore, advancements of co-processed excipients with better pricing are considered valuable to fulfil the increasing demand for low-cost excipients for generics and the growth of novel dosage forms in the future. Consequently, the prospect of co-processed excipients will still be focal point of research in academics and application in industries since the use of these excipients reduce formulation complexity in the drug development and manufacturing phase.
... Dua profil disolusi dinyatakan mirip apabila nilai f 2 berada pada kisaran 50-100.21 Parameter lain untuk menilai kemiripan profil pelepasan pelet yang tidak dikempa (uncompacted pellets atau UC) dan tablet MUPS (compacted pellets atau C) adalah menggunakan perbandingan nilai t 50 UC dengan t 50 C, di mana t 50 adalah waktu yang dibutuhkan bahan obat untuk terdisolusi 50% dari konsentrasi totalnya.22 Perhitungan nilai t 50 dilakukan dengan mengekstrapolasi garis linier dari profil disolusi kemudian garis linier tersebut dihitung persamaan regresinya (y=bx+a). ...
The compaction of multi-unit pellet system (MUPS) into tablets is a potential alternative for sustained release drugs. Tableting tools (punch and die) affect the compaction process and quality of MUPS tablets. The punch design intends to preserve the desired drug release of compacted pellets. This study aims to investigate the effect of two punch shapes, the flat face radius edge (FFRE) and concave-faced punch (concave), each at two different cup depths, on the physical properties and release profile of metformin HCl MUPS tablets. Drug release parameters, t50 values, showed that the metformin HCl released from MUPS tablets was faster than the uncompacted sustained release pellets. The similarity of the dissolution profile (f2) between MUPS tablets and uncompacted metformin HCl pellets was lower than 50 as the minimum acceptance value. The tablet tensile strength obtained was below the requirements (<1.7 MPa). Tablet disintegration time was approximately less than 2 minutes. In conclusion, drug release profile of the MUPS tablets showed damage of the pellets due to compaction process. Nevertheless, pellets compacted at low compaction pressure using FFRE with a deeper cup depth (size 0.80 mm) showed a slightly better protection compared to other punch shapes and cup depth sizes applied.
... Furthermore, the use of XPVP pellets would require the incorporation of pellet cushioning agents to mitigate the pellet coat damage. Various cushioning agents have been evaluated in previous studies [43,[71][72][73][74][75]. Future research could evaluate the effectiveness of these cushioning agents for XPVP pellets. ...
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.
... MCC + silica Dry coating Improved flowability and bulk density [17] MCC + silica Dry coating Improved tablet strength and drug-loading capacity [18] MCC + silicon dioxide Milling + dry coating Improved flowability, tablet ability and bulk density [19] MCC + alginic acid Wet granulation Improved flowability, tablet ability and disintegration time [20] MCC + lactose + starch Spray drying Improved flowability and compressibility [21] MCC + starch Spray drying Improved flowability and compressibility [22] MCC + manitol Spray drying Better flowability, less wetability [23] MCC + stearic acid Spray drying Act as a cushioning agent and prevents coat damage [24] MCC + crospovidone Extrusion Improved drug release, reduced plasticity [25] MCC: Microcrystalline cellulose. ...
Co-processing involves the incorporation of one excipients into the particle structure of other excipients to overcome the deficiencies of each excipients. The current patent describes the co-processing of microcrystalline cellulose and mannitol via fluid bed agglomeration with an aim to limit the use of lubricant in tablet composition. The co-processed excipients blend was compared with the physical blend of excipients and characterized for scanning electron microscopy, disintegration and hardness. The average particle size of co-processed excipients was less than 0.55 mm, characterized by large individual lactose coated particles whereas, the physical blend particles are uncoated and irregular in shape. Tablets made from both physical blend and co-processed excipients were compared. As per the hardness and disintegration studies, with increase in mixing time of excipients both hardness and disintegration time decreases.
... It has to be mentioned that although HPβCD accounts for high amount in spray dried particles, however, HPβCD is a plastic material (Suihko et al., 2000), the cushioning effect of HPβCD is not as strong as the elastic material SSG. The redispersion results indicated that the fillers in the compacts acted as the cushioning agents, which would decrease the impact of compaction stress on the particles (Li et al., 2016). Future studies should investigate the use of fragmenting and nonfragmenting excipients to support this hypothesis. ...
Oral delivery of nanoparticles possesses many advantages for delivery of active pharmaceutical ingredients (APIs) to the gastrointestinal tract. However, the poor physical stability of nanoparticles in liquid state is often a challenge. Removing water from the nanosuspensions and transforming the nanoparticles into solid particulate matter in the form of, e.g., tablets could be a potential approach to increase the stability of nanoparticles. The aim of this study was to transform nanoparticles into compacts and to investigate the redispersion of nanoparticles from compacts as well as the dissolution behavior of these compacts. DL-lactide-co-glycolide copolymer (PLGA) nanoparticles and celecoxib (CLX) nanoparticles were used as two model nanoparticle systems and fabricated into nano-embedded microparticles (NEMs) and subsequently compressed into compacts. The compacts were evaluated with respect to the redispersibility of the nanoparticles, as well as the dissolution characteristics of CLX. The results showed that the NEMs could be readily compressed into compacts with sufficient mechanical strength. The size of the redispersed PLGA nanoparticles from the compacts using 2-hydroxypropyl-β-cyclodextrin (HPβCD) as stabilizer was comparable to the original nanoparticles. In contrast, the redispersibility of CLX nanoparticles from the compacts was not as effective as for the PLGA nanoparticles evidenced by a significant increase in the size and polydispersity index (PDI) of the redispersed nanoparticles. Nonetheless, an obvious enhancement in dissolution rate of CLX was observed from the compacts with CLX nanoparticles. It is concluded that transforming polymeric nanoparticles into compacts via NEMs provides stabilization and allows redispersion into original nanoparticles. Despite the reduced redispersibility, compacts loaded with nanoparticles exhibited improved dissolution rate compared with the crystalline drug. Loading of nanoparticles into compacts is a promising approach to overcome the poor stability of nanoparticle within oral drug delivery of nanoparticles.
... Multiple approaches have long since been made to overcome these obstacles; most studies focus on finding the ideal cushioning particles (10). These efforts, while trying to avoid segregation with the application of larger tableting excipient particles (granules or pellets), also use a range of materials: from a special type of microcrystalline cellulose (MCC) (22), through additional excipients: from isopropyl alcohol (23) and polyethylene glycol (24) through lactose (12) or stearic acid (25) to wax (26,27). Another approach is to use a coating that is resistant to the high pressures exerted in the tableting machine; polyvinylpyrrolidone (28), polyvinyl acetate (29), and, surprisingly, metoprolol (30) have been used. ...
Most of the commercially available pharmaceutical products for oral administration route are marketed in the tablet dosage forms. However, compression of multiparticulate systems is a challenge for the pharmaceutical research and industry, especially if the individual unit is a coated particle, as the release of the active ingredient depends on the integrity of the coating. In the present study, polymer-coated pellets tableted with different types of excipients (powder, granules, pellets) then were investigated by various tablet-destructive (microscopic) and tablet non-destructive (microfocus X-ray; microCT) imaging methods. The information obtained from the independent evaluation of the in vitro drug release profiles model is confirmed by the results obtained by image analysis, regardless of whether X-ray or stereomicroscopic images of the coated, tableted pellets were used for image analysis. The results of this study show that the novel easy-to-use, fast, and non-destructive MFX method is a good alternative to the already used microscopic image analysis methods regarding the characterization of particulates, compressed into tablets.
... Furthermore, under the same force and stearic acid level, co-processed fillers showed higher compaction performance than the corresponding physical blends. Therefore, this co-spray drying method served as a step that not only ensured the cushioning effect of materials, but also good tableting performance and acceptable tablet disintegration time (94). ...
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.
... It was concluded that the optimal ratio of talc to be used is 1:4 (talc: Eudragit NE 30D). At this ratio, talc prevented any conglutination and enhanced the mechanical characteristics of the coating film to withstand the compaction forces applied during the tabletting process [56,57] ...
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.
... Regarding the compaction of multiple unit systems, such as pellets, ready-to-use excipient can be used to fill the void space between the pellets to be compressed and act as cushioning agent to absorb the compression force [10]. At the same time, filler materials can be employed to disperse individual pellets, preventing direct contact, by forming a layer around the pellets. ...
Compaction of multiparticulates into tablets, particularly into orodispersible tablets (ODTs), is challenging. The compression of pellets, made by solid lipid extrusion/spheronization processes, presents peculiar difficulties since solid lipids usually soften or melt at relatively low temperature ranges and due to applied mechanical forces. Until now, there are no reports in literature about the development of ODTs based on solid lipid pellets. To investigate the feasibility of producing such tablets, a design of experiment (DoE) approach was performed to elucidate the influence of compression force and amount of two co-processed excipients (Ludiflash® and Parteck® ODT) on properties of the tablets (friability, tensile strength, and disintegration time). ODTs (15 mm, flat-faced) with solid lipid pellets (250-1000 µm in diameter) containing 500 mg of metformin HCl, presenting immediate drug release profile and taste-masked properties, were targeted. During compression, a strong lamination of the tablets containing Parteck® ODT was observed. This phenomenon was prominently observed when high compression forces (≥ 5 kN) and high excipient amounts (≥ 40%; w/w) were used. On the other hand, the DoE focused on tablets with Ludiflash® showed better results regarding the production of ODTs. A positive influence of the compression force on the tensile strength, friability, and disintegration time of the tablets, regarding specifications of the Ph. Eur., was observed. The increase in the amount of this excipient resulted in fast disintegrating tablets, however, a negative influence on the tensile strength was noticed. After optimization of the parameters and formulation, based on the DoE results and considering the Ph. Eur. specifications for tablets, ODTs based on lipid pellets containing metformin HCl presenting immediate release profile (85% drug release in less than 30 min) and taste-masked properties (determined by an electronic tongue) were successfully obtained.
... 40 Cushioning excipients are developed using different techniques such as co-spray drying using stearic acid for the protection of pellets during compression. 41 Novel cushioning excipient developed using cospray dried micronized lactose with different polymers such as Hydropropylcellulose (HPC), Hydroxypropylmethylcellulose (HPMC) and polyvinylpyrrolidone (PVP). Such excipients help reducing yield pressure and improve compressibility. ...
Objective: The rationale for the study was to develop multiple unit pellet system (MUPS) of delayed release pantoprazole with desired physical properties and unaltered drug release profile from pellets even after compression into a fast disintegrating tablet.
Methods: In the presented study, delayed release pellets of pantoprazole were developed by two methods, i.e. extrusion-spheronization and drug layering techniques, coated using enteric polymer and subsequently compressed in to tablet. In drug layering technique, pantoprazole was loaded on Celphere®102 (microcrystalline cellulose spheres) as well as on Suglet® (sugar spheres) in fluid bed processor. Acid resistant polymer Eudragit
ND 30D was subsequently coated on each type of drug loaded pellets. Suitable tableting excipients were prepared such as soft pellets, Ceolus® (fibrous grade of microcrystalline cellulose) granules, Ludipress® (compressible lactose composition), Avicel® PH 200 and different combination of them. Various factors like property of pellets to be compressed, coating level, the composition of tableting excipient and ratio of drug-loaded pellets to tableting excipients were identified and optimized.
Results: MUPS with delayed releasing pellets of pantoprazole proved to provide sufficient hardness, rapid disintegration property, and unaltered release profile after compression. Delayed release pantoprazole pellets prepared by drug layering on celphere® 102 followed by coating with Eudragit® NE 30D showed better compressibility to withstand the drug release properties. The combination of Ceolus® granules and Ludipress (in 1:1 ratio) was found to be suitable tableting excipient that helped compression of pellets without rupturing polymeric coat. Pellets to excipients
ratio at 1:3 was found optimum.
Conclusion: Compaction behaviour of pantoprazole delayed-release pellets without loss of original delayed release profile was achieved by
formulating as MUPS based tablet of pantoprazole delayed release pellets using celephere® 102 was developed which was found suitable for desired release profile and physical properties.
... Thus, judicious selection and optimization ofthe fluid bed coating process are important. 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]. ...
Biriyani is a culinary dish cherished by millions around the globe. Time constraints, limited cooking facilities and the unavailability of authentic ingredients are just a few of the obstacles that can stand in the way of consuming a delicious and nutritious home-cooked meal. The current work intended to create solid dispersion-based pellets of biriyani spices. The growing demand for accessible and authentic culinary experiences encouraged innovation in the creation of these pellets. The development of biryani seasoning pellets represents a step forward in modernizing traditional cooking practices while honouring the heritage of biryani. This study focuses on the formulation and development of biryani seasoning pellets as a unique alternative for improving the convenience of biryani cooking while preserving its traditional flavour. In addition to their convenience, seasoning pellets provide health benefits due to their natural spice composition such as anti-inflammatory effects, improved digestion, increased metabolism and immune system support. These biryani seasoning pellets are a ready-to-use solution that entirely dissolves in hot rice, resulting in a tasty biryani experience with minimal preparation time. This study combines innovation and tradition addressing consumer needs for convenience and quality.
Hypertension is one of the major causes of mortality in the world. The non-selective -β-blocker which includes Timolol maleate (TM) is usually used in hypertension, at a given dose of 10–40 mg. The present research aims to design a tablet-in-tablet (TIT) formulation as a single-unit dosage form to achieve modified and rapid drug release. Wet granulation was used to create the inner core modified release tablet utilising the release modifying agent's Sodium alginate (SA) and Hydroxypropyl methylcellulose (HPMC K4M). The impact of independent factors, SA and HPMC K4M, in different percentages of w/w, which affect the in vitro drug release and swelling index, was investigated using a 3² complete factorial design. The TM outer instant-release shell, which was made using croscarmellose sodium and Microcrystalline cellulose (MCC) in three distinct sizes, was press-coated onto the optimised inner core tablet. The core and outer shell tablets are within acceptable ranges for several physicochemical properties. No indication of interactions between drugs, polymers, and excipients was found in the Fourier transform infrared (FTIR) and Differential scanning calorimetry (DSC) investigations. The inner core tablet's formulation F6 achieves a 96.38% in vitro drug release at 24 h and a swelling index of 52.7%. The TIT-2 was, however, considered as the final tablet-in-tablet formulation because contains fewer excipients and shorter disintegration time than TIT-3.
Microcrystalline cellulose (MCC) is one of the most popular cellulose derivatives in the pharmaceutical industry. Thanks to its outstanding tabletability, MCC is generally included in direct compression (DC) tablet formulations containing poor-tabletability active pharmaceutical ingredients. Nowadays, numerous grades of MCC from various brands are accessible for pharmaceutical manufacturers, leading to variability in MCC properties. Hence, it seems to be worthy and urgent to evaluate the influences of MCC variability on tablet quality and to identify critical material attributes (CMAs) based on the idea of Quality by Control. Besides, MCC-based co-processed excipients can effectively combine the functions of the filler, binder, disintegrant, lubricant, glidant, or flavor, and thus have drawn extensive interest. In this review, we focused specifically on the recent advances and development of MCC on DC tableting, including the functions in tablet formulations, potential CMAs, and MCC-based co-possessed excipients, therefore providing a reference for further studies.
Oral route of administration is widely accepted and desired because of its versatility, convenience, and most importantly patient compliance. Multiparticulate systems like granules and pellets are more advantageous when compared to single-unit dosage forms, as they are capable to distribute the drug more evenly in the gastrointestinal tract. The current paper focuses on pellets, the merits and demerits associated, various pelletization techniques, and its characterization. It also focuses on how pellets can be employed for drug delivery in controlled and sustained release formulations. It gives a com-plete emphasis on the drug and excipients that can be used in pellet formation, the marketed formulations, and the research pertaining to 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.
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.
In this study we present an approach that describes plasticity and deformation behavior of well-known materials based on analysis of plasticity, elasticity and fragmentary behavior. The powders were compressed using Korsch XP1, and the correlations between compaction and physical parameters were analyzed by canonical correlation analysis (CCA). Factor analysis (FA) was employed to normalize compaction work, yield pressure measurements (YP) and determine elastic stretch for all our sample; these were scored and ranked accordingly. The canonical variables showed that true density (rho(a)), compression degree (C-p) and mean particle size (D-50) were associated with plastic coefficient (PL), YP, and fast elastic stretch (FES). When factor scores were used in combination with original data, the plasticity of our samples was sorted and ranked as high, intermediate, or low, which are in accord with plasticity rankings previously reported in literature [10]. Hence, physical and compaction data interval was established that evaluated powder deformation behavior during compaction. Finally, FA was used to further characterize deformation behavior during compaction.
The basic objective of this study was to develop a novel technique that aids in compaction of coated pellets into tablets and obtain a release pattern from compressed pellets resembling the same pattern before compression.
Multi-unit dosage forms of mesalamine targeted to the colon were formulated by extrusion-spheronization, and then coated with Eudragit S (30%). These pellets were filled into gelatin capsules or further formulated and compressed into tablets. Tablets for colonic delivery of mesalamine were prepared by mixing the coated beads with cushioning agents like stearic acid and Explotab, or by applying an additional coat of gelatin (4% weight gain) onto the Eudragit S coated pellets, and then compressing into tablets (tableted reservoir-type pellets). Then additional coating of the tablets prepared by the coating technique was applied utilizing Eudragit L 100-55 (5% weight gain).
This technique provides additive protection for the coated beads to withstand the compression force during tableting. Excellent in vitro dissolution results were obtained, which were comparable to the results of the release of mesalamine from uncompressed beads filled in capsules. Mesalamine release from the capsules was 0.3% after 2 hours in gastric pH, 0.37% was released after an additional 1 hour in pH 6, and 89% was released after 1.5 hours in colonic pH 7.2.
Various formulation and process parameters have to be optimized in order to obtain tableted reservoir-type pellets having the same release properties as the uncompressed pellets. The coating technique delays the release of mesalamine until the beads reach the terminal ileum and colon. Once released in the colon, mesalamine is minimally absorbed and can act locally to treat ulcerative colitis.
The aim of this study was to characterize and evaluate a modified release, multiparticulate tablet formulation consisting of placebo beads and drug-loaded beads. Acetaminophen (APAP) bead formulations containing ethylcellulose (EC) from 40-60% and placebo beads containing 30% calcium silicate and prepared using 0-20% alcohol were developed using extrusion-spheronization and studied using a central composite experimental design. Particle size and true density of beads were measured. Segregation testing was performed using the novel ASTM D6940-04 method on a 50:50 blend of uncoated APAP beads (60%EC) : calcium silicate placebo beads (10% alcohol). Tablets were prepared using an instrumented Stokes-B2 rotary tablet press and evaluated for crushing strength and dissolution rate. Compared with drug beads (60%EC), placebo beads (10% alcohol) were smaller but had higher true densities: 864.8 mum and 1.27 g/cm(3), and 787.1 mum and 1.73 g/cm(3), respectively. Segregation testing revealed that there was approximately a 20% difference in drug content (as measured by the coefficient of variation) between initial and final blend samples. Although calcium silicate-based placebo beads were shown to be ineffective cushioning agents in blends with Surelease(R)-coated APAP beads, they were found to be very compactibile when used alone and gave tablet crushing strength values between 14 and 17 kP. The EC in the APAP bead matrix minimally suppressed the drug release from uncoated beads (t(100%) = 2 h). However, while tablets containing placebo beads reformulated with glycerol monostearate (GMS) showed a slower release rate (t(60%)= 5 h) compared with calcium silicate-based placebos, some coating damage ( approximately 30%) still occurred on compression as release was faster than coated APAP beads alone. While tablets containing coated drug beads can be produced with practical crushing strengths (>8 kP) and low compression pressures (10-35 MPa), dissolution studies revealed that calcium silicate-based placebos are ineffective as cushioning agents. Blend segregation was likely observed due to the particle size and the density differences between APAP beads and calcium silicate-based placebo beads; placebo bead percolation can perhaps be minimized by increasing their size during the extrusion-spheronization process. The GMS- based placebos offer greater promise as cushioning agents for compacted, coated drug beads; however, this requires an optimized compression pressure range and drug bead : placebo bead ratio (i.e., 50:50).
OBJECTIVE: To study correlation between physical properties and compressibility and compactablility of Microcrystalline cellulose. METHODS: After determining the physical properties such as particle size distribution, moisture capacity, angle of repose, bulk density, tapped density, the powder was tableted by the Korsch XP1 at the same filling height, and data derived from heckle model, plasticity constant, cumulative elastic recovery, tensile strength and it's changes with time were evaluated. RESULTS: The physical properties of microcrystalline cellulose had great effect on its compactablility as well as cumulative elastic recovery out of die, but not on compressibility. And pressure applied correlated closely with changes of tensile strength in storage, which was intensified by the influence of water in powder on the particle size. CONCLUSION: Microcrystalline cellulose shows excellent compressibility, however, particle size reduction is able to decrease the compactability. Since the water in powder can increase particle size by changing internal structure of particles and plays a prerequisite role in lubrication and adherence, the variation of water content may weaken the compatability of microcrystalline cellulose and worsen the mechanical strength stability of tablets in storage.
The effects of liquid spray rate and atomizing pressure on the size of spray droplets and spheroids were investigated in this study. The range of droplet sizes tended to narrow and relatively smaller droplets were formed at higher atomizing pressures. When liquid spray rate was increased, the droplets were larger and had a wider size range. Although alterations in liquid spray rate could affect spray droplet size, greater changes in droplet size were achieved by varying atomizing pressure. In these investigations, changes in spray droplet size and atomizing pressure did not appear to greatly affect mean spheroid size. However, the presence of an atomizing pressure was necessary for the even distribution of the moistening liquid to reduce localized overwetting during spheronization by rotary processing. The amount of oversized particles may thus be decreased and a more uniformly sized yield may be achieved with the use of relatively higher atomizing pressures. With a fixed volume of moistening liquid sufficient for spheronization, larger spheroids were produced with increasing liquid spray rates. The increased wetting per unit time resulted in the formation of larger nuclei and enhanced the growth rate of spheroids.
The wet-state particle size of microcrystalline cellulose (MCC) dispersed in different moistening liquids was characterized to elucidate the effect of moistening liquid type on the extent of MCC particle de-aggregation. Cohesive strength of moistened MCC masses was also assessed and pellet production by extrusion-spheronization attempted. MCC dispersed in alcohol or water-alcohol mixtures with higher alcohol proportions generally had larger particle sizes. Moistened mass cohesive strength decreased and poorer quality pellets were obtained when water-alcohol mixtures with higher alcohol proportions were used as the moistening liquid. MCC comprise aggregates of small sub-units held together by hydrogen bonds. As MCC particle de-aggregation involves hydrogen bond breaking, moistening liquids with lower polarity, such as water-alcohol mixtures with higher alcohol proportions, induced lesser de-aggregation and yielded MCC with larger particle sizes. When such water-alcohol mixtures were employed during extrusion-spheronization with MCC, the larger particle size of MCC and lower surface tension of the moistening liquid gave rise to moistened masses with lower cohesive strength. During pelletization, agglomerate growth by coalescence and closer packing of components by particle rearrangement would be limited. Thus, weaker, less spherical pellets with smaller size and wider size distribution were produced.
The bioavailability of ibuprofen from pellets based on microcrystalline wax and starch derivatives was tested. During the in vivo evaluation an oral dose of 300 mg ibuprofen was administered to healthy human volunteers. F-1 and F-2 pellets were filled into hard gelatin capsules and were formulated with 60% ibuprofen, 15% waxy maltodextrin and 25% wax (a mixture of Lunacera M® and Lunacera P® (ratio 7/3) in the case of F-1 pellets and pure Lunacera P® in case of the F-2 pellets). In vitro, t50% was 20 and 4 h for F-1 and F-2 pellets, respectively. Both formulations behaved in vivo as sustained release formulations with a HVDt50%Cmax value of 6.4 and 5.6 h for F-1 and F-2, respectively. Bioavailability depended on the composition of the formulation as the Cmax-values were 5.3 and 8.5 μg/ml and the AUC0→24h-values 49.0 and 75.6 μg×h/ml for the F-1 and F-2 pellets, respectively. The bioavailability of a chewable tablet, made of F-3 pellets (30% ibuprofen, 40% drum dried corn starch and 30% Lunacera P®) and showing an immediate in vitro drug release, was similar to the bioavailability of an ibuprofen suspension. The Cmax and AUC0→24h of F-3 pellets were 31.9 μg/ml and 121.1 μg×h/ml, respectively. These data demonstrate that pellets based on the combination of microcrystalline wax and starch derivatives can be used to formulate sustained as well as immediate release formulations.
This article presents two new equations that evaluate the difference between the percent drug dis-solved per unit time for a test and a reference formulation. In essence, the equations provide a single value to describe the "closeness" of two dissolution profiles. Comparing the in vitro dissolution profiles of a tablet, powder, or capsule provides the formulator with the critical information necessary to screen formulations during product development; evaluate stability; and optimize dosage forms. Curve comparisons can produce the means to evaluate the effect that changing a process variable has upon dissolution. Comparing profiles may also be useful as a quality assurance tool to measure batch-to-batch uniformity. This article is based partly on a poster presentation given at the Ninth Annual AAPS Meeting. One of the equations presented in this article has been adopted in the SUPAC guidelines and is published in the 30 November 1995 Federal Register.
Spheroids are usually produced by a multi-step extrusion-spheronization process. The single-step production of spheroids may be carried out in a rotoprocessor. The use of feed materials in powder form requires an adaptation of the spheronizer machinery. This study investigates the formation and growth of spheroids and the changes in the spheroid moisture content in a single-step agglomeration-spheronization method. There was a rapid increase in size and formfactor values when spheroids started to form and grow from the powder mix. Although there was a continual and considerable loss of moisture with time, this did not have an appreciable effect on spheroid size and shape after the spheroid formation stage as the spheroid structure had already been determined. Spheroid size increased with higher liquid spray rates. The use of higher gap air pressures resulted in a greater rate of moisture loss and the production of smaller spheroids.
The effect of moisture content of microcrystalline cellulose (MCC) on the compression properties of systems containing this diluent, has been examined. The formulations used included a product containing 97% MCC and two MCC based direct compression systems containing 49.5% paracetamol and 68% potassium phenethicillin. The MCC used contained moisture levels ranging from 0.6 - 7.3%. The tablets were made on an instrumented machine in conditions of relative humidity not exceeding 40%. The following tablet MCC are well documented, little has been published on the effect of moisture on its compressional characteristics. Also since it is common industrial practice to dry excipient before use with moisture sensitive drugs, a study of the effect of MCC on its compressional, disintegration and dissolution properties should be useful.
There has been considerable interest in making tablets from spheronized bead rather than through encapsulation. It is obvious that the forces present during compaction may break a coating intended to control drug release. This effect may be moderated by cushioning agents incorporated into the bead formulation or situation between the beads. Our work describes the latter method.
Drug release data were used as an indirect method to study the possible protective effect of different excipients on the tableting of theophylline granules coated with Eudragit RS. Under our experimental conditions the order of least damage to the coating was: polyethylene glycol 3350 < microcrystalline cellulose < crospovidone < lactose < dicalcium phosphate. These results are in good agreement with the yield values of these materials. It seems that the tablet matrix has a lower yield pressure than the pellet/pellet coating, such that the energy of compaction is absorbed by the matrix, and that the matrix is preferentially deformed. Under our experimental conditions, and even at very low compressional pressure there is always damage of the coating membranes. Nevertheless, by appropriate selection of the excipients, it is possible to achieve a formulation to ensure minimum damage to this coating. To this end, a combination of the following excipients with low yield pressure values is proposed as a suitable excipient mixture for coated particles: microcrystalline cellulose 50%, polyethylene glycol 3350 25% and crospovidone 25%.
Physical properties and theophylline-release profiles of compressed tablets prepared with amorphous waxy maize starches dried using different methods were examined. A gelatinized waxy maize starch paste (10% solids in water) was either freeze-dried or oven-dried (40 or 105°C) until the moisture content reached to <5%. To form the tablets, the dried amorphous starch powders, either with or without theophylline (3 : 10, w/w), were remoistened to a water content of (17 ± 0.2)%, and compressed into tablets. The drying process applied to the amorphous starch powders affected both the compactness and swelling behavior of the tablets. Although no crystallinity was detected in all the starches tested, X-ray diffraction patterns indicated that starch chains dried at the lower temperature (40°C) are allowed more time to re-associate during the drying process than those dried at the higher temperature (105°C). The freeze-dried starch powders formed tablets characterized by greater compactness and rigidity than was observed in the oven-dried starch samples. The drug release of the tablets prepared with the starch dried at the higher temperature (105°C) occurred at a much slower rate than that of the tablets made with the starch dried at the lower temperature (40°C). The drug release characteristics of the freeze-dried starch tablets were nearly identical to those of the tablets prepared with the starch dried at 105°C. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2007
The influence of the composition and properties of pellets on the properties of the tablets prepared from their mixtures has been evaluated. Three types of pellets were prepared, (a) those containing a model drug readily identifiable by colour, to evaluate tablet consistency; (b) those containing a deformable material, glyceryl monostearate, to provide pressure absorbing and binding properties, and (c) those containing an inorganic disintegrating agent. Tablets from various mixtures of these pellets, in a statistical designed manner, were prepared at a known compression force and their weight uniformity, friability, diametral breaking load and disintegration times were measured. The uniformity of composition of selected tablets was also determined. Analysis of variance established that the disintegrant type, the proportion of drug pellets and the proportion of disintegrant pellets influenced the breaking load and the disintegration time of the tablets. The proportion of drug and disintegrant pellets influenced the tablet friability whereas the type of disintegrant did not. Canonical analysis failed to establish an exact relationship between pellet properties and tablet properties. However some conclusions can be drawn from this analysis. First, an increase in either the amount of drug pellets or disintegrant pellets decreases the tablet breaking load, and the disintegration times are reduced. Secondly, disintegration times are increased with disintegrants of a high density. Thirdly, larger amounts of drug and disintegrant pellets increase the tablet friability.
Enteric-coated sucrose pellets containing a layer of bisacodyl beneath the coating were compressed into tablets on an instrumented single-punch machine using four different filler-binders for direct compression. Different copolymers based on polymethacrylates were applied as coatings. Pellets of two different crushing strengths were used. The quality of the films before and after tableting was evaluated by determining the amount of bisacodyl liberated after treatment for 2 h in 0.1 M HC1 according to the requirements of USP 23 for enteric-coated preparations. Results indicate that the most important parameters are the coating agent itself and the amount of coating applied to the pellets. Higher coating weights and coatings with better elastic properties lead to formulations, which liberate less bisacodyl after compression. Formulations are available that fulfil all requirements of USP 23 regarding entericcoated preparations.
Model placebo multiple unit oral dosage forms were prepared by the processes of extrusion and spheronisation. The non-invasive technique of gamma scintigraphy was used to monitor the gastrointestinal transit of these radiolabelled dosage forms. Standard sized units (1.18–1.40 mm) of density 2.0 and 2.4 g cm−3 were compared with similarly sized control units of 1.5 g cm−3. Each density was tested separately in eight healthy fasted male subjects. The results showed no differences in the gastrointestinal transit of the three formulations as measured by each of several parameters selected to describe the process. However, the results did reveal some interesting features of the gastric emptying process, and provide further information regarding the critical density at which a prolongation of gastric emptying occurs.
This work aimed to explore the potential of lactose as novel cushioning agents with suitable physicomechanical properties by micronization and co-spray drying with polymers for protecting coated multi-particulates from rupture when they are compressed into tablets. Several commercially available lactose grades, micronized lactose (ML) produced by jet milling, spray-dried ML (SML), and polymer-co-processed SMLs, were evaluated for their material characteristics and tableting properties. Hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), and polyvinylpyrrolidone (PVP) at three different levels were evaluated as co-processed polymers for spray drying. Sugar multi-particulates layered with chlorpheniramine maleate followed by an ethylcellulose coat were tableted using various lactose types as fillers. Drug release from compacted multi-particulate tablets was used to evaluate the cushioning effect of the fillers. The results showed that the cushioning effect of lactose principally depended on its particle size. Micronization can effectively enhance the protective action of lactose. Although spray drying led to a small reduction in the cushioning effect of ML, it significantly improved the physicomechanical properties of ML. Co-spray drying with suitable polymers improved both the cushioning effect and the physicomechanical properties of SML to a certain degree. Among the three polymers studied, HPC was the most effective in terms of enhancing the cushioning effect of SML. This was achieved by reducing yield pressure, and enhancing compressibility and compactibility. The combination of micronization and co-spray drying with polymers is a promising method with which new applications for lactose can be developed.
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.
The compression behavior of high- and low drug strength pellets containing kappa-carrageenan as pelletisation aid was investigated. Model drugs and fillers with different compression mechanisms were used and the effects of compression force and turret speed were examined. Regardless of the compression behavior of their starting components, all pellet formulations exhibited minimal to absent fragmentation and underwent compression by deformation, confirmed by increased equivalent diameter and aspect ratio and decreased roundness factor of the pellets retrieved after de-aggregation of tablets prepared from lubricated pellets. The retrieved pellets showed also higher fracture resistance in three of the tested formulations and no statistically significant difference in the remaining one thus excluding significant crack formation. A densification mechanism was suggested by decreased total porosity and reduced median pore radius of the compressed pellets. No effect of the process parameters on the degree of pellet deformation was reported. The tensile strength of the tablets prepared from unlubricated pellets increased slightly with increased compression force. Compression of pellets with high density silicified microcrystalline cellulose (SMCC HD 90) as embedding powder protected them from severe deformation and resulted in tablets with sufficient tensile strength, minimal friability, negligible elastic recovery and short disintegration time. The percentage of the pellets and the compression force affected the tensile strength of the prepared tablets whereas no influence of the turret speed and the pre-compression force was observed.
Effects of calcium silicate (disintegration-promoting agent) and various lubricants on an optimized beta-cyclodextrin-based fast-disintegrating tablet formulation were investigated. Effects of moisture treatment were also evaluated at 75, 85 and 95% relative humidities. A two factor, three levels (3(2)) full factorial design was used to optimize concentrations of calcium silicate and lubricant. Magnesium stearate, being commonly used lubricant, was used to optimize lubricant concentration in optimization study. Other lubricants were evaluated at an obtained optimum concentration. Desiccator with saturated salt solutions was used to analyze effects of moisture treatments. Results of multiple linear regression analysis revealed that concentration of calcium silicate had no effect; however concentration of lubricant was found to be important for tablet disintegration and hardness. An optimized value of 1.5% of magnesium stearate gave disintegration time of 23.4 s and hardness of 1.42 kg. At an optimized concentration, glycerol dibehenate and L-leucine significantly affected disintegration time, while talc and stearic acid had no significant effect. Tablet hardness was significantly affected with L-leucine, while other lubricants had no significant effect. Hardness was not affected at 75% moisture treatment. Moisture treatment at 85 and 95% increased hardness of the tablets; however at the same time it negatively affected the disintegration time.
The strength of lactose tablets has been measured by application of the diametral-compression test. The relative value of tensile, compressive, and shear stresses within the tablet varies, depending on the characteristics of the tablets and the surface providing the applied compression. It has been shown that to obtain reproducible results for the strength of tablets prepared at a given compression force, the tablet must break in such a manner that the tensile stress is the major stress. For a given tablet, this may require the placing of suitable padding material between the tablet and the compressing surfaces. Assessment of the type of failure can be made visually and under the correct conditions, the results expressed as a tensile strength. There are, however, a range of conditions which ensure tensile failure resulting in different values for the tensile strength. These values are characteristic of the tablet and test conditions and are not absolute values of tensile strength.
Microcrystalline cellulose (MCC) was pulverized with a vibrational rod mill. The degree of crystallinity of MCC decreased from 65.5 to 12.1% with pulverization time due to mechanochemical effect. Pulverized MCCs were compressed at 155.6 MPa using a compression test apparatus, and the two parameters relating to compactability, the B value and yield pressure, were calculated using a Heckel plot. These values were lowered as the degree of crystallinity of MCC became smaller. These results suggest that the crystal region and the amorphous region in MCC particles may be mainly fractured and deformed plastically during compression, respectively. Then the dissolution test was performed for the acetaminophen-MCC (10:90) tablets. Dissolution profiles showed an interesting phenomenon, namely, the dissolution rate of acetaminophen from MCC tablet decreased when the degree of crystallinity of MCC was in the range from 65.5 to 37.6%, however, it increased markedly when the degree of crystallinity of MCC was in the range from 25.8 to 12.1%. The amount of water absorbed into tablets changed in accord with the dissolution rates of acetaminophen from tablets. The dissolution data indicate that drug release can be modified by changing the degree of crystallinity of MCC.
Placebo particles were mixed with film-coated diltiazem pellets to evaluate them as cushioning agents during tabletting in order to protect the film coat from damage. The cushioning properties of alpha-lactose monohydrate granules, microcrystalline cellulose pellets and wax/starch beads were evaluated by comparing the dissolution profile of the coated pellets before and after compression (compression force 10 kN). Only the tablet formulations containing wax/starch beads provided protection to the film coat. However, the dissolution rate of tablets formulated with waxy maltodextrin/paraffinic wax placebo beads was too slow as the tablets did not disintegrate. Adding 50% (w/w) drum-dried corn starch/Explotab/paraffinic wax beads to the formulation was the optimal amount of cushioning beads to provide sufficient protection for the film coat and yield disintegrating tablets. Using a compression simulator, the effect of precompression force and compression time on the dissolution rate was found to be insignificant. The diametral crushing strength of tablets containing 50% (w/w) drum-dried corn starch/Explotab/paraffinic wax beads was about 25.0 N (+/-0.3 N), with a friability of 0.4% (+/-0.04%). This study demonstrates that adding deformable wax pellets minimizes the damage to film-coated pellets during compression.
In this study, reservoir pellets were prepared and their compression behaviour as well as the importance of their porosity for compression-induced changes in drug release was investigated. Pellets of three different porosities, consisting of microcrystalline cellulose and salicylic acid, were prepared by extrusion-spheronisation and spray-coated with ethyl cellulose (ethanol solution). Lubricated reservoir pellets were compressed and retrieved by deaggregation of the tablets. The retrieved pellets were analysed regarding porosity, thickness, surface area, shape and drug release. It was found that the coating did not significantly affect their compression behaviour. Compaction of pellets of high original porosity considerably affected densification and degree of deformation, whereas the effect on drug release was minor. For low porosity pellets the influence of compaction on drug release was appreciable, but only slight regarding densification and degree of deformation. In conclusion, the porosity of pellets is a potential factor that the formulator can use to optimize drug release and one that can affect the robustness of a formulation during manufacture. Moreover, the coating may be able to adapt to the densification and deformation of the pellets.
The effect of wax on the deformation behavior and compression characteristics of microcrystalline cellulose (Avicel PH-101) and acetaminophen (APAP) beads is described. Beads of Avicel PH-101 and APAP formulations were prepared using extrusion and spheronization technology. A waxy material, glyceryl behenate, N.F. (Compritol), was added to the formulations in amounts ranging from 10% to 70% of total solid weight. Beads with a selected particle size range of 16-30 mesh were compressed with an instrumented single punch Manesty F press utilizing a 7/16-in. flat-faced tooling set. Compaction profiles were generated for the tablets to evaluate the effect of wax on the densification of beads containing wax. Beads made without wax (the control formulation) required greater compression forces to form cohesive tablets. As the amount of wax in the bead formulation was increased, the beads become more plastic and compressible. The Heckel equation which relates densification to compression pressure was used to evaluate the deformation mechanisms of the bead formulations. The analysis shows that as the level of wax in the bead formulation is increased, the yield pressure decreases, indicating that the beads densify by a plastic deformation mechanism.
Fluidized-bed manufactured enteric-coated diclofenac sodium pellets were compressed into tablets. The blend of two aqueous acrylic resins dispersion in different ratios, Eudragit NE30D and Eudragit L30D-55, were used to prepare enteric-coated diclofenac sodium pellets of different particle sizes and coating level. The cushioning pellets with different properties and these enteric-coated pellets were compressed into tablets in different proportions. The drug release of the tablets containing these pellets would be lower than 10% in 2 h in simulated gastric fluid, but reach (83 +/- 2.42)% in 1 h in simulated enteric fluid. The mixture of Eudragit NE30D and Eudragit L30D-55 could be used to prepare enteric pellets which are suitable for compression. The cushioning pellets which were composed of stearic acid/microcrystalline cellulose (4:1, w/w) could avoid rupture of the coating of pellets during the compression.
The effect of wax on compaction of micro crystalline cellulose beads by extrusion and spheronisation
- Nd Illoanusi
- Jb Schwartz
Compaction properties of directly compressible materials
- M Celik
A new enteric tablet of acetylsalicylic acid: biopharmaceutical aspects
- Jp Decheshe
- L Delattre
Cushioning wax beads for making solid shaped articles
- J P Remon