Compaction Studies on Beads: Compression and Consolidation Parameters

Abstract

The purpose of this work was to evaluate compaction of the beads containing microcrystalline cellulose (MCC). Although MCC in its powder form is universally recognized as a very compressible material, studies in these laboratories demonstrated that MCC beads prepared by extrusion/spheronization were not. In fact, MCC beads are very hard and not easily deformable or broken. Therefore, the objectives of this work were to modify the bead composition by incorporating materials which might change the bead compactibility and to describe the effects. The dissolution properties of the compacted forms were also evaluated.

To study the compaction behavior of the MCC beads it was necessary to modify the Athy-Heckel equation to describe compression and to combine that analysis with the Leuenberger equation to describe consolidation.     

Compaction Properties of Spheronized Binary Granular Mixtures

Two spheronized granular formulations containing 20% anhydrous lactose/80% microcrystalline cellulose (MCC) and 80% anhydrous lactose/20% microcrystalline cellulose were blended in various proportions and compressed. Physical-mechanical properties of the resulting compacts were investigated using tableting indices and compared with powder mixtures of the same compositions. The compacts were compressed at a solid fraction of 0.80 for both powder and bead mixtures. An additional set of bead compacts were made at a solid fraction of 0.87. The thickness of the compacts was measured in the post-ejection stage to investigate their expansion behavior. The tensile strength with and without a stress concentrator and the dynamic indentation hardness of the compacts were determined. The brittle fracture index (BFI) and bonding index (BI) values were also calculated. The microstructure of the beads and compacts were investigated using scanning electron microscopy to observe the bonding phenomena. The results showed that the compacts made from beads underwent different compaction/consolidation behaviors than the powders of the same lactose/MCC compositions. For powdered compacts, the tensile strength with or without a stress concentrator increased with increasing MCC content while the compacts made from beads showed the opposite trend. However, this trend was not seen in the indentation hardness test. The resulting BFI values were all low due to the plastic nature of the materials selected. The BI values of the bead and powder compacts also exhibited opposite tendencies and reflected the divergent mechanical properties of the materials presented in granulated and powdered forms. Microstructure studies revealed the bonding states between the beads in the compacts. Discrepancies in mechanical properties were related to the compressibility, compactibility, and porosities of the excipients studied.     

Bead compacts. II. Evaluation of rapidly disintegrating nonsegregating compressed bead formulations

In this study, three techniques for the prevention or mitigation of polymer coat fracture on compaction of sustained-release beads into tablets were investigated. All techniques in this paper were evaluated without the addition of any cushioning excipients, but rather by spray coating these excipients to avoid segregation during product manufacturing. First, it was shown that use of swellable polymers such as polyethylene oxide (PEO) serves a unique and effective role in preventing polymer coat rupture. PEO was spray coated between the ethylcellulose (EC) and microcrystalline cellulose (MCC) coats to evaluate its cushioning effect. The compacted PEO layered beads, on dissolution, disintegrated into individual beads with sustained drug release of up to 8 hr. It is postulated that the PEO was hydrated and formed a gel that acts as a sealant for the cracks formed in the ruptured polymer coating (sealant-effect compacts). Second, EC-coated drug-layered beads were also overcoated with cushioning excipients such as polyethylene glycol (PEG) and MCC with an additional coating of a disintegrant. These beads were compressed at pressures of 125, 500, and 1000 pounds into caplets and, on dissolution testing, disintegrated into individual beads when the dissolution medium was switched from simulated gastric to intestinal fluid. The dissolution profiles show that the polymer coat was partly disrupted on compaction, leading to a total drug release in 8-10 hr. Third, EC-coated beads were also granulated with cushioning excipient and compressed. This approach also resulted in a ruptured polymer coat on the beads, but at higher compaction pressure produced a partially disintegrating matrix caplet that showed a nearly zero-order sustained drug release for 24 hr. The effect of bead size and polymer coat thickness was also investigated.     

Binder effectiveness for beads with high drug levels

Previous reports from these laboratories showed that microcrystalline cellulose (Avicel^R MCC, PH-101) formulations with low and medium drug levels (10 and 50%) produced very uniform beads whereas formulations containing MCC with high drug levels (80%) were difficult to process without special treatment or required the incorporation of alternate excipients. In this study, several binders, at a 2% level, specifically: Carbomer (Carbopol^R 934-P), Sodium carboxymethylcellulose (CMC 7MF), Hydroxypropylcellulose (Klucel^R HXF), Methylcellulose (Methocel^R K-15). Povidone, USP (PVP K29-32) and Pregelatinized starch NF (Starch 1500^R), were evaluated to determine whether they might impart advantages in processing and whether any differences in dissolution behavior would result. Spheres containing 80% anhydrous theophylline, the binders and MCC were manufactured by the extrusion/marumerization technique. In general, beads containing high drug levels produced with these binders are suitable for further processing (coating). Processing ease, bead shape, and bead hardness (friability) varied with the choice of binder. Beads with carbomer, hydroxypropylcellulose, and methylcellulose remained intact during dissolution testing; beads with starch, carboxymethylcellulose, PVP, and the control did not.     

Binder effectiveness for beads with high drug levels

Abstract

Previous reports from these laboratories showed that microcrystalline cellulose (Avicel^R MCC, PH-101) formulations with low and medium drug levels (10 and 50%) produced very uniform beads whereas formulations containing MCC with high drug levels (80%) were difficult to process without special treatment or required the incorporation of alternate excipients. In this study, several binders, at a 2% level, specifically: Carbomer (Carbopol^R 934-P), Sodium carboxymethylcellulose (CMC 7MF), Hydroxypropylcellulose (Klucel^R HXF), Methylcellulose (Methocel^R K-15). Povidone, USP (PVP K29-32) and Pregelatinized starch NF (Starch 1500^R), were evaluated to determine whether they might impart advantages in processing and whether any differences in dissolution behavior would result. Spheres containing 80% anhydrous theophylline, the binders and MCC were manufactured by the extrusion/marumerization technique. In general, beads containing high drug levels produced with these binders are suitable for further processing (coating). Processing ease, bead shape, and bead hardness (friability) varied with the choice of binder. Beads with carbomer, hydroxypropylcellulose, and methylcellulose remained intact during dissolution testing; beads with starch, carboxymethylcellulose, PVP, and the control did not.     

Formulation and Compaction of Nonfracturing Deformable Coated Beads

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.     

Formulation and Compaction of Nonfracturing Deformable Coated Beads

Abstract

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.     

Formulation and characterization of a compacted multiparticulate system for modified release of water-soluble drugs--part 1--acetaminophen

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).     

The effect of wax on compaction of microcrystalline cellulose beads made by extrusion and spheronization

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.     

Formulation and Characterization of a Compacted Multiparticulate System for Modified Release of Water-Soluble Drugs – Part 1 Acetaminophen

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 μm and 1.27 g/cm³, and 787.1 μm and 1.73 g/cm³, 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^®-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 (～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).     

How to maintain the morphology of styrene-divinylbenzene copolymer beads during the sulfonation reaction

This work aims to describe the use of acetyl sulfate as sulfonating reagent of microporous beads based on styrene (STY) and divinylbenzene (DVB) which were prepared by aqueous suspension copolymerization. The copolymer was chemically modified by two different sulfonating agents, namely sulfuric acid and acetyl sulfate which is prepared “in situ” by mixing acetic anhydride and sulfuric acid. The morphologic features of resin beads were analyzed by optical microscopy (OM) and by scanning electron microscopy (SEM). The sulfonic group incorporation into the copolymer network was verified by infrared spectroscopy (FTIR) and quantified by using a standardized NaOH solution. The bead morphology maintenance depends on the sulfonating agent and reaction conditions.     

A new method to destruct targeted cells using magnetizable beads and pulsed magnetic force

We investigated a new method to destruct targeted cells using magnetizable beads and pulsed magnetic force. The cells were combined with the beads by an antigen-antibody reaction (cell/bead/antibody complex), aggregated by a magnet, and stimulated by a magnetic stimulator. The viability of the aggregated and stimulated cell/bead/antibody complexes was significantly decreased, and the cells were destructed by the penetration of the beads into the cells or rupturing of the cells by the beads. These results suggest that magnetic aggregation and pulsed magnetic stimulation can effectively damage only the cells targeted by an antigen-antibody reaction.     

Compaction Properties of Microcrystalline Cellulose Using Tableting Indices

The compaction properties of microcrystalline cellulose (MCC) from 6 different sources were investigated and compared using tableting indices. The 50-μm and 100-μm grades were studied in order to determine lot-to-lot variability within a source, variability between sources, and the influence of storage conditions on the compaction properties of MCC. Two lots of each grade of MCC were obtained from each source and tested as received. It was found that the Avicel and Emcocel products demonstrated the most similarities based on tableting indices. Significant lot-to-lot differences in the tableting indices were observed for Fibrocel, Omnicel, and Spectrum MCC products. The brittle fracture index was low for all products tested and not significant. Storage of compacts at elevated humidity conditions prior to determining the tableting indices decreased the magnitude of the tensile strength, dynamic indentation hardness, and bonding index. Particle size analysis revealed differences between the labeled mean particle size and the experimentally determined value for some of the MCC grades and sources investigated. The percent weight gain of MCC powder at 18 hr was less than 0.6% at 30% relative humidity, and ranged from about 0.75% to 1.46% at 51% and 75% relative humidities. The x-ray diffraction patterns were similar for the MCC grades and sources investigated. MCC products from different sources are not directly substitutable based on the differences in physicomechanical properties observed for the tableting indices.     

Automated bead alignment apparatus using a single bead capturing technique for fabrication of a miniaturized bead-based DNA probe array

We have developed an automated bead alignment apparatus for fabricating a bead-based DNA probe array inside a capillary. The apparatus uses 16 micro vacuum tweezers to extract single beads from among a large amount of beads in bead stock wells. It then manipulates single beads into the probe array capillaries. Single 100-microm-diameter beads were successfully extracted from the water-contained bead-stock well by the vacuum tweezers, which have inner and outer diameters of 50 and 150 microm. An interesting aspect is that unexpected extra beads adsorbed on the outer wall of the vacuum tweezers can be removed using the surface tension force between the water and the atmosphere. In testing the total performance of this apparatus, the DNA probe arrays with 10 sets of probe-conjugated beads and 2 plain beads were produced in the intended order in the capillaries. The time needed to align the 12 beads was 10 min, and the 16 bead arrays were fabricated simultaneously. After hybridization experiments using these fabricated DNA probe arrays, fluorescence from each bead was clearly observed.     

Chitosan-Alginate Multilayer Beads for Gastric Passage and Controlled Intestinal Release of Protein

Abstract

Chitosan-alginate beads loaded with a model protein, bovine serum albumin (BSA) were investigated to explore the temporary protection of protein against acidic and enzymatic degradation during gastric passage. Optimum conditions were established for preparation of homogenous, spherical, and smooth chitosan-alginate beads loaded with BSA. Multilayer beads were prepared by additional treatment with either chitosan or alginate or both. The presence of chitosan in the coagulation bath during bead preparation resulted in increased entrapment of BSA. During incubation in simulated gastric fluid (SGF pH 1.2), the beads showed swelling and started to float but did not show any sign of erosion. Inclusion of pepsin in the gastric fluid did not show a further effect on the properties of the beads. Release studies were done in simulated gastric fluid (SGF pH 1.2) and subsequently in simulated intestinal fluid (SIF pH 7.5) to mimic the physiological gastrointestinal conditions. After transfer to intestinal fluid, the beads were found to erode, burst, and release the protein. Microscopic and macroscopic observations confirmed that the release of protein was brought about by the burst of beads. Chitosan-reinforced calcium-alginate beads showed delay in the release of BSA. The multilayer beads disintegrated very slowly. The enzymes pepsin and pancreatin did not change the characteristics of BSA-loaded chitosan-alginate beads. Single layer chitosan-alginate beads released 80–90% of the model protein within 12 h while multilayer beads released only 40–50% in the same period of time. The release from chitosan-alginate beads and multilayer beads in SIF was further delayed without prior incubation in SGF. It is concluded that alginate beads reinforced with chitosan offer an excellent perspective for controlled gastrointestinal passage of protein drugs.     

Nanorheology of regenerated silk fibroin solution

We have investigated the rheological properties of regenerated silk fibroin (RSF), a viscoelastic material at micro and nano length scales, by video microscopy. We describe here the principles and technique of video microscopy as a tool in such investigations. In this work, polystyrene beads were dispersed in the matrix of RSF polymer and the positions of the embedded beads diffusing were tracked using video microscopy. An optical tweezer was used to transport and locate the bead at any desired site within the micro-volume of the sample, to facilitate the subsequent free-bead video analysis. The position information of the beads was used to obtain the time dependant mean squared displacement (MSD) of the beads in the medium and hence to calculate the dynamic moduli of the medium. We present here the results of rheological measurements of the silk polymer network in solution over a frequency range, whose upper limit is the frame capture rate of our camera at full resolution. The technique is complementary to other microrheological techniques to characterize the material, but additionally enables one to characterize local inhomogeneities in the medium, features that get averaged out in bulk characterization procedures.     

Chitosan-alginate multilayer beads for gastric passage and controlled intestinal release of protein

Chitosan-alginate beads loaded with a model protein, bovine serum albumin (BSA) were investigated to explore the temporary protection of protein against acidic and enzymatic degradation during gastric passage. Optimum conditions were established for preparation of homogenous, spherical, and smooth chitosan-alginate beads loaded with BSA. Multilayer beads were prepared by additional treatment with either chitosan or alginate or both. The presence of chitosan in the coagulation bath during bead preparation resulted in increased entrapment of BSA. During incubation in simulated gastric fluid (SGF pH 1.2), the beads showed swelling and started to float but did not show any sign of erosion. Inclusion of pepsin in the gastric fluid did not show a further effect on the properties of the beads. Release studies were done in simulated gastric fluid (SGF pH 1.2) and subsequently in simulated intestinal fluid (SIF pH 7.5) to mimic the physiological gastrointestinal conditions. After transfer to intestinal fluid, the beads were found to erode, burst, and release the protein. Microscopic and macroscopic observations confirmed that the release of protein was brought about by the burst of beads. Chitosan-reinforced calcium-alginate beads showed delay in the release of BSA. The multilayer beads disintegrated very slowly. The enzymes pepsin and pancreatin did not change the characteristics of BSA-loaded chitosan-alginate beads. Single layer chitosan-alginate beads released 80-90% of the model protein within 12 h while multilayer beads released only 40-50% in the same period of time. The release from chitosan-alginate beads and multilayer beads in SIF was further delayed without prior incubation in SGF. It is concluded that alginate beads reinforced with chitosan offer an excellent perspective for controlled gastrointestinal passage of protein drugs.     

聚丙烯/微晶纤维素复合材料的非等温结晶动力学研究

用熔融复合法制备聚丙烯/微晶纤维素复合材料,用DSC法研究其非等温结晶行为,分别用Jeziorny法、Ozawa法和Mo法对所得的数据进行处理.结果表明,Jeziorny法和Mo法处理非等温结晶过程比较理想,MCC的加入缩短了t1/2,起到了异相成核作用.     

Bead Compacts. I. Effect of Compression on Maintenance of Polymer Coat Integrity in Multilayered Bead Formulations

Abstract

Little information is available on the comparability of beads for oral sustained-release dosage forms. It is known that polymer-coated beads may fuse together to produce a non-disintegrating controlled-release matrix tablet when compressed. This study evaluates the effect of compression on beads with multiple layers of polymer and drug coat, and the effect of cushioning excipients and compaction pressure on drug release from compressed bead formulations. The multilayered beads consist of several alternating layers of acetaminophen (APAP) and polymer coats (Aquacoat®) with an outer layer of mannitol as a cushioning excipient. Percent drug release versus time profiles showed that the release of drug decreases from noncompacted beads as the amount and number of coatings increases, with only 43% of drug released in 24 hr for coated beads with 10 layers. It was shown that the compacted multilayered beads will disintegrate in gastrointestinal fluids, providing a useful drug release pattern. It was shown that beads of drug prepared by any method can be spray-layered with excipients such as Avicel and mannitol. Spray-layering of the cushioning excipient onto beads can provide an effective way to circumvent segregation issues associated with mixing of the polymer-coated beads and powdered or spherical/nonspherical cushioning excipients. Spray layering of the cushioning excipient can also provide excellent flow properties of the final formulation as visually observed in our experiments. Triple-layered caplets (TLC) were also prepared with outer layers of Avicel PH-101 or polyethylene oxide (PEO), and a center layer of polymer-coated beads. For TLC, the polymer coating on the beads fractured, and nondisintegrating matrix formulations were obtained with both caplet formulations.     

Characterization of calcium alginate beads containing structurally similar drugs

The aim of this study was to investigate the characteristics of alginate beads prepared by ionotropic gelation in which structurally similar drugs were incorporated. For this purpose theophylline and theobromine were selected as model drugs. The influence of incorporated drugs on bead characteristics such as size, shape, and morphology, as well as encapsulation efficiency, was examined. It was found that theobromine as well as theophylline content in beads significantly decreased with increasing hardening time due to drug diffusion into the hardening media. In theobromine beads the drug content was extremely improved by dropping the alginate and drug solution into an acidic calcium chloride solution, while theophylline content was to some extent improved by the hardening of beads in a calcium chloride solution saturated with the drug. The most evident difference between theophylline and theobromine beads was in their shape and morphology. Theobromine beads were round, while theophylline ones had an irregular shape with an extremely wrinkled surface. The distinction in shape was highly dependent on drug content. Additionally, it was demonstrated that beads' shape was dependent on preparation conditions as well. On the basis of x-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) analyses and scanning electron microscope (SEM) photographs it was found that the most of the drug in bead was present in an amorphous state. Therefore, it is suggested that some drug-alginate interactions could be present in beads and might be responsible for the different shape of theophylline and theobromine beads.

Thus it can be concluded that the preparation of beads by ionotropic gelation cannot be generalized even though structurally similar drugs are incorporated.