Investigation of critical factors affecting mechanical characteristics of press-coated tablets using a compaction simulator.

Press-coated tablets have become an indispensable dosage form in chronotherapeutic drug delivery. Drug release from press-coated tablets has been extensively studied, yet there is little knowledge about their mechanical characteristics. This study aimed to systematically investigate the effects of critical factors on the structure, layer adhesion, and delamination tendency of the tablets. Material elasticity was found to play an important role in determining tablet structure in that excessive elastic mismatch between core and shell materials caused tablet defects during decompression and ejection. Unlike bilayer tablets, the overall strength of press-coated tablets was more affected by binding capacity of coating materials than by the core properties. Shell/core ratio was another factor affecting tablet integrity against external stresses. To mitigate the risk of delamination, poor layer adhesion must be compensated by increasing the coating thickness or enhanced by optimizing the formulation and process (e.g., core plasticity/brittleness, initial core solid fraction, and compression speed). X-ray micro-computed tomography revealed the presence of a shell-core gap and inhomogeneous density distribution within the tablet where the side coat appeared as the least dense and weakest region. These findings will enable the improvement of tablet quality and widen the application of press coating in industrial manufacturing.

Systematic approach to elucidate compaction behavior of acyclovir using a compaction simulator.

In this research, various approaches were attempted with a compaction simulator to investigate the unidentified compaction behavior of acyclovir, a model compound. Various indicators for the compaction behavior of acyclovir were obtained and compared with those of three commonly used excipients with relatively well-known compaction behavior. From two frequently used powder compaction models, the Heckel and Walker models, curvature of plot, yield stress, D0, SRS value, and W value were acquired. In addition, compression and elastic energies were obtained during the loading and unloading phases, respectively. The ratio of the two energies was also utilized. To characterize the mechanical properties of materials during bond formation, the radial tensile strength of powder compacts was measured. For all evaluations, the effects of compaction rate and lubrication were studied simultaneously. We found that primary particles of acyclovir were compacted mainly by plastic flow, with high viscoelasticity and low particle interactions. Their bond formation was highly sensitive to strain rate and lubrication. This study showed the potential application of a compaction simulator to elucidate the compaction behavior of a material of interest.

Swellable and porous bilayer tablet for gastroretentive drug delivery: Preparation and in vitro-in vivo evaluation.

The purpose of this study was to develop a novel gastroretentive drug delivery system with immediate buoyancy and high wet strength. The proposed bilayer tablet was composed of a drug layer and a highly porous and swellable gastroretentive (GR) layer. The highly porous GR layer was prepared by sublimating the volatile materials after compaction with swellable polymers. This pore-forming process decreased the density of the GR layer and enabled the tablet to float immediately on the dissolution media. The GR layer formulation was optimized by comparing the swelling, erosion, and mechanical properties of candidate swellable polymers. The release rates were conveniently controlled by changing the polymer content in the drug layer, while the swelling and floating properties were provided by the GR layer. The application of percolation theory revealed that the polymer content above the estimated threshold was required for a reliable drug release profile. In vivo study in fed beagle dogs confirmed the enhanced gastric retention time of the tablets compared to that of conventional single layer tablets. Taken together, our data suggest that the proposed system can be a promising platform technology with superior GR properties and a convenient formulation process.

Use of roller compaction and fines recycling process in the preparation of erlotinib hydrochloride tablets.

This study focuses on improving the manufacturing process for a generic immediate-release tablet containing erlotinib hydrochloride by adding a fines recycling process during roller compaction. Due to the large fraction of small-sized API particles, the starting powder mixture was inconsistently fed into the roller compactor. Consequently, poorly flowing granules with a high ratio of fines were produced. A fines recycling step was, therefore, added to the existing roller compaction process to minimize the risks caused by the poor granule flow. A laboratory scale roller compactor and a tablet simulator were used to prepare granules at various process conditions. The effect of dry granulation parameters on size distribution, API distribution, powder flow, compaction properties, and dissolution profile was evaluated. The granule batch after fines recycling had markedly improved size distribution and flowability while maintaining acceptable tablet tensile strength and rapid dissolution profile. The application of the fines recycling process at commercial scale resulted in reliable dissolution performance and batch-to-batch consistency, which were further confirmed by bioequivalence to the reference product. Understanding how granule properties are impacted by the fines recycling process may enable fine-tuning of the dry granulation process for optimal product quality.

Formulation and evaluation of carrier-free dry powder inhaler containing sildenafil.

Pulmonary delivery of sildenafil for the treatment of pulmonary arterial hypertension could overcome the limitations of intravenous and oral administration routes, such as poor patient compliance and systemic side effects. In this study, a carrier-free dry powder inhaler (DPI) formulation was developed, using spray drying technique and L-leucine as a dispersibility enhancer. Sildenafil citrate salt and sildenafil free base were evaluated for drug transport using a Calu-3 cell model, and their suitability for DPI production by spray drying was tested. Characteristics of the resultant carrier-free DPI powders were examined, namely crystallinity, morphology, size distribution, density, zeta potential, and aerodynamic performance. A Box-Behnken design was adopted to optimize the formulation and process conditions, including leucine amount, fraction of methanol in spraying solvent, and inlet temperature. While both sildenafil forms exhibited sufficient permeability for lung absorption, only sildenafil base resulted in DPI powders which were stable for 6 months. The introduction of leucine into the formulations effectively enhanced aerodynamic performance of the powders and particles with favorable size, shape, and density were produced. The optimal DPI formulation determined from experimental design possesses excellent aerodynamic performance with 89.39% emitted dose and 80.08% fine particle fraction, indicating the possibility of incorporating sildenafil into carrier-free DPIs for pulmonary delivery.

Development of sustained-release microparticles containing tamsulosin HCl for orally disintegrating tablet using melt-adsorption method.

In this study, using the melt-adsorption method, we developed sustained-release microparticles containing the potent drug, tamsulosin HCl, for use as orally disintegrating tablets. A high-speed kneading granulator was used, enabling temperature modulation and uniform material distribution. A lipid and ethylcellulose suspension (Surelease®) was applied to retard drug release, and magnesium aluminometasilicate (Neusilin®) was used as adsorbent. Among various lipid candidates for melt-adsorption, beeswax and glyceryl behenate were selected due to their high mechanical strength. Hot stage microscopy and powder X-ray diffraction analysis results showed compatibility between tamsulosin HCl and both lipids. Characteristic adsorption behavior was observed depending on the physicochemical properties of each composition. Especially, the specific surface area of Neusilin® decreased with increasing amounts of Surelease®, attributed to the pore-covering effect of Surelease®, which significantly increased the size of the microparticles after the lipid adsorption. For a Surelease®-to-beeswax ratio 1:50, both the desired particle size distribution and low burst release were achieved. Furthermore, the orally disintegrating tablet containing optimized microparticles had acceptable tablet hardness and rapid disintegration. Herein, the feasibility of melt-adsorption for the preparation of sustained-release microparticles was well demonstrated. With its convenience and efficiency, the proposed method is a promising alternative to conventional methods, which are relatively difficult and time consuming.

Preparation and optimization of glyceryl behenate-based highly porous pellets containing cilostazol.

The aim of this study was to prepare a highly porous multiparticulate dosage form containing cilostazol for gastroretentive drug delivery. The floating pellets were prepared with glyceryl behenate as a matrix former and camphor as a sublimating agent by extrusion/spheronization and sublimation under vacuum. Granules prepared with sublimation at 60 °C displayed a slower dissolution rate and smoother surface morphology than those prepared at lower temperatures. This was unexpected as the reported melting point of glyceryl behenate is higher than 69 °C. The DSC study revealed that melting began at a lower temperature owing to the multicomponent property of glyceryl behenate, which led to a sintering effect. The prepared pellets were spherical with unimodal size distribution. They also had porous structures with increased porosity, which led to immediate buoyancy. As cilostazol is a hydrophobic drug that has an erosion-based release mechanism, drug release profile was highly correlated with the percentage of disintegrated pellets. Various excipients were added to the glyceryl behenate-based formulation to increase the floating duration. When hydroxyethyl cellulose was added to the glyceryl behenate-based pellets, acceptable dissolution rate and buoyancy were acquired. This system could potentially be used for gastroretentive delivery of various hydrophobic drugs, which was generally considered difficult.

Application of continuous twin screw granulation for the metformin hydrochloride extended release formulation.

This study focuses on evaluating the potential of transferring from a batch process to continuous process for manufacturing of the extended release formulation. Metformin hydrochloride (HCl) was used in the model formulation which was intended to contain the high amount of hydrophilic drug. The effects of barrel temperature, binder type, powder feed rate, and screw speed on granule properties (size and strength) and torque value in twin screw granulation were investigated. Due to the high content of hydrophilic model drug, the granules prepared at a higher temperature with HPMC binding solution had the narrower size distribution and greater strength than the granules prepared with distilled water as a binding solution. After continuous drying and milling steps, the granules (continuous process) satisfied the fundamental purpose of granulation with size and flowability, despite different shape compared with the granules (batch process). Furthermore, there were no significant differences between two granulation processes in tablet properties, such as tablet hardness and in vitro release. The considerations and strategies used in this study to transfer from a batch to continuous process can be applied to other existing formulations based on high shear granulation to enable rapid process transfer in the pharmaceutical industry.

Release kinetics of highly porous floating tablets containing cilostazol.

This study focuses on developing a highly porous floating tablet containing cilostazol. The underlying release mechanism of cilostazol from porous and floating tablets in dissolution media containing surfactants was investigated. The tablets were prepared by compressing granules and excipients with a sublimating agent, followed by sublimation under vacuum. The volatile material for the sublimating agent was chosen based on its flow properties using conventional methods as well as the twisted blade method. Resultant tablets could float immediately and had significantly higher tensile strengths than conventional tablets of similar porosities, holding a promising potential for increasing gastroretentive properties. Fitting the release profiles to the Korsmeyer-Peppas equation indicated Super Case II, Case II and non-Fickian kinetics, which implied that the release was affected by both floating behavior and matrix erosion. Abrupt changes in release kinetic parameters and erosional behaviors were found between the tablets containing different amounts of HPMC, indicating the existence of an excipient percolation threshold. Neither the surfactant in the media nor the porosity affected the dominant release mechanism, which was matrix erosion. Understanding the dominant release mechanism and percolation threshold allows for tuning the formulation to obtain various release profiles.