A Method for the Tensile Strength Prediction of Tablets with Differing Powder Plasticities.

Tablets are the most commonly used dosage form in the pharmaceutical industry, and their properties such as disintegration, dissolution, and portability are influenced by their strength. However, in industry, the mixing fraction of powders to obtain a tablet compact with sufficient strength is determined based on empirical rules. Therefore, a method for predicting tablet strength based on the properties of a single material is required. The objective of this study was to quantitatively evaluate the relationship between the compression properties and tablet strength of powder mixtures. The compression properties of the powder mixtures with different plasticities were evaluated based on the force-displacement curves obtained from the powder compression tests. Heckel and compression energy analyses were performed to evaluate compression properties. During the compression energy analysis, the ratio of plastic deformation energy to elastic deformation energy (Ep/Ee) was assumed to be the plastic deformability of the powder. The quantitative relationship between the compression properties and tensile strength of the tablets was investigated. Based on the obtained relationship and the compression properties of a single material, a prediction equation was put forward for the compression properties of the powder mixture. Subsequently, a correlation equation for tablet strength was proposed by combining the values of K and Ep/Ee obtained from the Heckel and compression energy analyses, respectively. Finally, by substituting the compression properties of the single material and the mass fraction of the plastic material into the proposed equation, the tablet strength of the powder mixture with different plastic deformabilities was predicted.

Enhancement of cell membrane permeability by using charged nanoparticles and a weak external electric field.

Because the cell membrane is the main barrier of intracellular delivery, it is important to facilitate and control the translocation of extracellular compounds across it. Our earlier molecular dynamics simulations suggested that charged nanoparticles under a weak external electric field can enhance the permeability of the cell membrane without disrupting it. However, this membrane permeabilization approach has not been tested experimentally. This study investigated the membrane crossing of a model compound (dextran with a Mw of 3000-5000) using charged nanoparticles and a weak external electric field. A model bilayer lipid membrane was prepared by using a droplet contact method. The permeability of the membrane was evaluated using the electrophysiological technique. Even when the applied electric field was below the critical strength for membrane breakdown, dextran was able to cross the membrane without causing membrane breakdown. These results indicate that adding nanomaterials under a weak electric field may enhance the translocation of delivery compounds across the cell membrane with less damage, suggesting a new strategy for intracellular delivery systems.

Development of a Simple In-Die Method for Determination of Capping Tendency in Rotary Tableting Machines.

A rotary tableting machine is used for the continuous tableting process. Tableting conditions often result in capping, leading to serious problems during production. Several studies have been conducted to predict the tablet capping tendency. However, as most previous studies were conducted using a compaction simulator, there is a lack of technology that can be readily applied during actual production. Therefore, the present study aimed to develop a novel method for predicting tablet capping in a rotary tableting machine. We hypothesized that capping occurs when residual stress of the tablet inside a die exceeds the critical stress immediately before ejection. Residual stress was evaluated by measuring the in-line die-wall pressure in a rotary tableting machine. Additionally, critical stress was estimated from the tablet strength inside the die using the Rumpf's equation. The critical and residual stresses were compared to determine the capping tendency to some extent. The findings of this study will substantially contribute to the rapid detection of tablet capping during tablet production.

Continuous measurement of die wall pressure in a rotary tablet machine.

In the pharmaceutical industry, tablets are manufactured using rotary tableting machines. Recently, die wall pressure in a single-punch press was measured to understand the compaction mechanism and predict tableting failure. However, die wall pressure measurements in rotary tableting machines have not been studied. Two challenges exist in measuring die wall pressure in these machines, viz. (i) lack of space inside the machine to set up the measurement equipment and (ii) difficulty in installing wired measurement hardware because the die rotates with the rotary plate. This study aimed to continuously measure die wall pressure in a rotary tableting machine and investigate the effect of high compression speed on die wall pressure. Die wall pressure at tableting speeds of up to 140 mm/s was successfully determined using a wireless telemeter. Residual die wall pressure for plastic materials was strongly dependent on the tableting speed, although the tableting speed affected the maximum die wall pressure minimally. This novel measurement technique can be used to study the effect of tableting speed on die wall pressure, which can be applied in solving the problems of capping and lamination during tablet production.

Mechanism of Solubility Enhancement of Poorly Water-Soluble Drugs Triggered by Zeolitic Imidazolate Frameworks.

Numerous efforts have been devoted to improving the solubility of poorly water-soluble drugs. Recently, it was reported that the use of metal-organic frameworks (MOFs), which are a new class of porous materials consisting of metal ions and organic ligands, is effective in improving the solubility of poorly water-soluble drugs. Our previous study demonstrated an improvement in the solubility of indomethacin (IDM) triggered by the zeolitic imidazolate framework-8 (ZIF-8). The present study aimed to elucidate the solubilization mechanism using the ZIF series, namely, ZIF-8, ZIF-67, and ZIF-L. It was confirmed that the solubility of ZIF-trapped IDM and ibuprofen (IBU) was enhanced compared to the raw drugs, regardless of the ZIF type. This study focused on 2-methylimidazole (2-MIM), which is commonly used as a ZIF organic ligand. Both IDM and IBU were easily dissolved by the addition of 2-MIM, suggesting that the presence of 2-MIM enhanced the solubility of the drugs. Inductively coupled plasma measurements also confirmed the presence of metal ions of ZIFs in the supernatant solution after the drug release tests, indicating the decomposition of ZIFs during drug release. The findings of this study demonstrated the solubilization mechanism of poorly water-soluble drugs using ZIF particles. We observed that the drugs loaded on the ZIFs were released simultaneously with the decomposition of some of the ZIFs. The 2-MIM molecules were also released concurrently. The presence of 2-MIM improved the solubility of poorly water-soluble drugs.

Direct translocation of a negatively charged nanoparticle across a negatively charged model cell membrane.

Nanoparticles have attracted much attention as a carrier for drug, gene, and macromolecule delivery in next-generation biomedical and therapeutic technologies. In delivery applications, nanoparticles tend to have negative charge due to the negative charge of biomolecules used as delivery cargo, while biological cell membranes are also negatively charged. This means that negatively charged nanoparticles (NC-NPs) are required to translocate across these negatively charged cell membranes (NC-CMs). However, this translocation is unlikely to occur because of electrostatic interactions. Here, we investigated the translocation of a NC-NP across a NC-CM under a transmembrane electric potential through coarse-grained molecular dynamics simulations. To model the transmembrane potential, two approaches were adopted: externally applied electric field and ionic charge imbalance. We showed that a NC-NP can directly translocate across a NC-CM via a non-disruptive pathway under a weak external electric field with an ionic charge imbalance. It was also found that the ionic charge imbalance contributes to the membrane crossing of a NC-NP as well as the self-resealing of the cell membrane after a NC-NP translocation. Our findings imply that NC-NPs can be delivered into a cell by combining applied electric field with membrane hyperpolarization/depolarization induced by an external stimulus.

Numerical Study on Spray Drying Process: Effect of Nonuniform Temperature Field and Interaction between Droplets on Evaporation Rates of Individual Droplets.

Spray drying process is widely used to produce particulate materials in the pharmaceutical industries, such as porous materials for direct compression, solid dispersion for improvement of drug dissolution properties, micro encapsulation to stabilize active compounds, taste masking, preparation of dry powder for inhalation. However, as many factors affect the physical properties of dried particles and the spray drying processes have complex behaviors in which heat and mass transfer occur simultaneously, the detailed mechanisms of dry particle generation have yet to be sufficiently elucidated. In this study, computational fluid dynamics was used to simulate water droplet evaporation in a spray dryer, and the evaporation kinetics of "individual droplets" in the droplet aggregate (group) were analyzed. The numerical simulation revealed that each droplet had different evaporation rates owing to the following two reasons. First, the driving force of evaporation, ΔT, changed every moment as the droplets traveled through different temperature fields in the drying tower. Second, it was calculated the driving force for droplet evaporation differed from the ideal system because the evaporation of other droplets changed the fluid characteristics around the droplets. The obtained results are important findings that lead to the understanding the spray drying process to design and manufacture the pharmaceutical products.

Numerical Study on Particle Adhesion in Dry Powder Inhaler Device.

This study investigated the particle adhesion mechanism in a capsule of dry powder inhaler (DPI) based on a combined computational fluid dynamics and discrete element method (CFD-DEM) approach. In this study, the Johnson-Kendall-Roberts (JKR) theory was selected as the adhesion force model. The simulation results corroborated the experimental results-numerous particles remained on the outlet side of the capsule, while a few particles remained on the inlet side. In the computer simulation, the modeled particles were placed in a capsule. They were quickly dispersed to both sides of the capsule, by air fed from one side of the capsule, and delivered from the air inlet side to the outlet side of the capsule. It was confirmed that vortex flows were seen at the outlet side of the capsule, which, however, were not seen at the inlet side. Numerous collisions were observed at the outlet side, while very few collisions were observed at the inlet side. These results suggested that the vortex flows were crucial to reduce the amount of residual particles in the capsule. The original capsule was then modified to enhance the vortex flow in the area, where many particles were found remaining. The modified capsule reduced the number of residual particles compared to the original capsule. This investigation suggests that the CFD-DEM approach can be a great tool for understanding the particle adhesion mechanism and improving the delivery efficiency of DPIs.

Numerical study for tableting process in consideration of compression speed.

A numerical study of the tableting process using a finite element method (FEM) is important to quantitatively understand the structural change inside the tablet and the mechanism of tableting failures such as capping, picking, lamination, and sticking. In the pharmaceutical field, the Drucker-Prager Cap (DPC) model is used most widely to demonstrate the mechanical behavior of the powder during tableting. The DPC model, however, cannot consider compaction speed, although the compaction speed has a large impact on the tablet strength and tableting failures. In the present study, a combined novel model using both the DPC and Perzyna models, which incorporates a visco-plastic behavior considering the compression speed, was proposed and numerical simulation was conducted. Cellulose, lactose, and acetaminophen were selected as model powders. The DPC-Perzyna model parameters were determined from experimental compaction tests, unconfined compression tests, and tension tests. The calculated loading curves agreed with the experimental data under different compaction speeds, in addition the high compression speed resulted in less plastic deformation and much residual stress. It was demonstrated that the DPC-Perzyna model proposed in the present study was useful to analyze the tableting process when considering compression speed.

Effect of Particle-Wall Interaction and Particle Shape on Particle Deposition Behavior in Human Respiratory System.

Dry powder inhalation (DPI) has attracted much attention as a treatment for respiratory diseases owing to the large effective absorption area in a human respiratory system. Understanding the drug particle motion in the respiratory system and the deposition behavior is necessary to improve the efficiency of DPI. We conducted computer simulations using a model coupling a discrete element method and a computational fluid dynamics method (DEM-CFD) to evaluate the particle deposition in human respiratory system. A simple artificial respiratory model was developed, which numerically investigated the effect of particle properties and inhalation patterns on the particle deposition behavior. The DEM-CFD simulations demonstrated that the smaller- and lower-density particles showed higher reachability into the simple respiratory model, and the particle arrival ratio to the deep region strongly depended on the aerodynamic diameter. The particle arrival ratio can be described as an exponential function of the aerodynamic diameter. Furthermore, the exponential relationship between the particle reachability into the depth of the simple respiratory model and the aerodynamic diameter predicted the particle aerodynamic diameter based on the required reachability. The particle shape also had an impact on the particle deposition behavior. The rod-like particles with a larger aspect ratio indicated higher reachability into the depth of the simple respiratory model. This was attributed to the high velocity motion of the particles whose long axis was in the direction of the deep region.

Direct translocation of nanoparticles across a model cell membrane by nanoparticle-induced local enhancement of membrane potential.

In biomedical technologies that use nanoparticles, the nanoparticles are often required to translocate across a cell membrane. Application of an external electric field has been used to increase the cell membrane permeability; however, damage to the cell is of great concern. Using a molecular dynamics simulation, we show that even under a weak external electric field that is lower than the membrane breakdown intensity, a cationic nanoparticle will directly translocate across a model cell membrane without membrane disruption. We then reveal its physical mechanism. At the contact interface between the nanoparticle and the cell membrane, the electric potential across the membrane is locally enhanced by superimposing the nanoparticle surface potential on the externally applied potential, resulting in its direct translocation. Our finding implies that, by controlling the nanoparticle-induced local enhancement of the membrane potential, the cellular delivery of nanoparticles via a non-endocytic and non-disruptive pathway can be realized.

Continuous synthesis of nano-drug particles by antisolvent crystallization using a porous hollow-fiber membrane module.

The synthesis of nano-size drug particles by antisolvent crystallization using a porous hollow fiber membrane provides promising benefits such as the capability of continuous operation, low energy input, and ease of scale-up for a variety of industrial processes. Porous hollow fiber membranes have also been shown to produce more efficient mixing than conventional mixing equipment mostly because in mixing binary fluids, they provide sufficient mixing time, retention time, and a large contact interface for the drug solution and the antisolvent, allowing for the precise control of nucleation and crystal growth necessary to form nano-size particles. This study reports an experimental and numerical approach to obtain a further understanding of the fundamental principles of antisolvent crystallization using a porous hollow fiber membrane. This includes producing a particle size-controlled drug nanosuspension experimentally using a commercial microfiltration (MF) pencil scale module, and a numerical analysis of mixing behavior using a computational fluid dynamics (CFD) simulation. From the results obtained, a nanosuspension of a model drug, Indomethacin, with particles of average diameter 0.320 µm was prepared. Furthermore, this nanosuspension has higher stability and a much lower tendency to agglomerate as compared to simple mixing of the anti-solvent and drug solution. Results from the numerical simulation showed that micromixing is possible using the porous hollow fiber membrane even under the most compromising conditions.