Sticking Detection by Repeated Compactions on a Single Tablet.

"Sticking" during tablet manufacture is the term used to describe the accumulation of adhered tablet material on the punch over the course of several compaction cycles. The occurrence of sticking can affect tablet weight, image, and structural integrity and halt manufacturing operations. The earlier the risk of sticking is detected during R&D, the more options are available for mitigation and the less potential there is for significant delays and costs. The detection osf sticking, however, during the early stages of drug development is challenging due to the limitations of available material quantity. In this work, single tablet multi-compaction (STMC) and a highly sensitive laser reflection sensor are used to detect the propensity of sticking with ibuprofen powder blends. STMC can differentiate the various formulations and replicates the trends of sticking at different punch speeds. The results demonstrate the potential for STMC to be used as an extremely material sparing (requiring very few tablets) methodology for the assessment of sticking during early-stage development.

Scanning Electron Microscope Observations of Powder Sticking on Punches during a Limited Number (N < 5) of Compactions of Acetylsalicylic Acid.

PURPOSE: To obtain quantitative information and mechanistic insight into the problem of sticking of acetylsalicylic acid tablets on a metallic punch. METHODS: Low voltage scanning electron microscopy was used to observe punch area coverage and morphology of adhered powder on a flat punch used for a limited number of compactions. RESULTS: Material accumulation in terms of area coverage of the punch per compaction cycle was determined at two pressures over five compactions. The distribution of the adhered material on the punch was non-uniform with more material left on the center of the punch. The sizes of the adhered particles range from 1 to 100 µm, with 50% of the punch surface coverage from particles of an equivalent diameter > 30 µm. Three types of adhered particles were identified after the first compaction: (a) fragments of initial particles with very high aspect ratio, (b) nearly equiaxed fragments with multiple cracks, (c) heavily deformed islands of low profile. Some preliminary ideas that explain these observations are presented and discussed. CONCLUSIONS: The ability of SEM to provide quantitative information on sticking from few compactions presents an interesting possibility for a material sparing technique that provides insight on the propensity of sticking.

Bone mineral (31)P and matrix-bound water densities measured by solid-state (31)P and (1)H MRI.

Bone is a composite material consisting of mineral and hydrated collagen fractions. MRI of bone is challenging because of extremely short transverse relaxation times, but solid-state imaging sequences exist that can acquire the short-lived signal from bone tissue. Previous work to quantify bone density via MRI used powerful experimental scanners. This work seeks to establish the feasibility of MRI-based measurement on clinical scanners of bone mineral and collagen-bound water densities, the latter as a surrogate of matrix density, and to examine the associations of these parameters with porosity and donors' age. Mineral and matrix-bound water images of reference phantoms and cortical bone from 16 human donors, aged 27-97 years, were acquired by zero-echo-time 31-phosphorus ((31)P) and 1-hydrogen ((1)H) MRI on whole body 7T and 3T scanners, respectively. Images were corrected for relaxation and RF inhomogeneity to obtain density maps. Cortical porosity was measured by micro-computed tomography (µCT), and apparent mineral density by peripheral quantitative CT (pQCT). MRI-derived densities were compared to X-ray-based measurements by least-squares regression. Mean bone mineral (31)P density was 6.74 ± 1.22 mol/l (corresponding to 1129 ± 204 mg/cc mineral), and mean bound water (1)H density was 31.3 ± 4.2 mol/l (corresponding to 28.3 ± 3.7 %v/v). Both (31)P and bound water (BW) densities were correlated negatively with porosity ((31)P: R(2) = 0.32, p < 0.005; BW: R(2) = 0.63, p < 0.0005) and age ((31)P: R(2) = 0.39, p < 0.05; BW: R(2) = 0.70, p < 0.0001), and positively with pQCT density ((31)P: R(2) = 0.46, p < 0.05; BW: R(2) = 0.50, p < 0.005). In contrast, the bone mineralization ratio (expressed here as the ratio of (31)P density to bound water density), which is proportional to true bone mineralization, was found to be uncorrelated with porosity, age or pQCT density. This work establishes the feasibility of image-based quantification of bone mineral and bound water densities using clinical hardware.

Understanding the effect of environmental history on bilayer tablet interfacial shear strength.

PURPOSE: To understand the effect of post production environmental conditions on the interfacial strength of bilayer tablets. METHODS: Bilayer tablets of microcrystalline cellulose/dicalcium phosphate were exposed to several humidity conditions higher/lower than production conditions and tested in shear to assess interfacial strength. Specific failure mechanisms were observed using x-ray microtomography and scanning electron microscopy. RESULTS: Transients in moisture diffusion of bilayer tablets with significant differential moisture absorption characteristics are responsible for the reduction of strength in both high and low moisture environments. X-ray microtomography and SEM experiments have shown that two different mechanisms of interfacial crack formation are present. For low moisture exposure, interfacial cracks close to the surface were produced, whereas at high moisture conditions, internal interfacial cracks were created. In both cases the fracture modes are consistent with the tensile stresses that develop locally due to the volumetric strains induced by moisture absorption. CONCLUSIONS: The insight gained from this work will be useful for material selection and packaging of bilayer tablet systems. While additional work is needed to develop specific guidelines for the optimization of bilayer strength, the results presented here provide a rational basis upon which such work can be conducted.

Effect of Tensile Stresses on the Evolution of Post-Compaction Properties of Sodium Chloride Tablets and Its Mixtures.

This study focuses on the effect of moisture on the strength of tablets of sodium chloride (NaCl) and its mixtures after compaction. We built on our prior work that proposed an explanation of the strengthening of NaCl tablets due to a dissolution-reprecipitation mechanism and the decrease in strength of NaCl-starch tablets due to the presence of residual stresses on NaCl-NaCl contacts in the mixture. Here, we offer experimental evidence that induced tensile stresses on NaCl slow down or negate (if large enough) the strengthening mechanism. Based on the idea of the negative role of tensile residual stresses in NaCl mixtures, we prove experimentally that NaCl-X mixtures can be optimized in terms of post-compaction strength, if the elastic properties of the second component in the mixture match that of NaCl.

On the Post-Compaction Evolution of Tensile Strength of Sodium Chloride-Starch Mixture Tablets.

This study focuses on the evolution of mechanical behavior of starch and sodium chloride (NaCl) mixture tablets after compaction. This type of mixture has attracted attention in the past because such tablets exhibit lower tensile strengths than the ones of its individual components. Here we demonstrate that the strengths of NaCl-starch mixtures and NaCl tablets evolve after compaction in an opposite way. When stored at relative humidity of 60%, NaCl tablets strengthen with time, whereas NaCl-starch mixtures weaken. To explain this behavior, we propose that in the NaCl-starch mixture, the presence of 2 materials with significantly different elastic moduli leads to creation of tensile stresses at the stiffer NaCl-NaCl contacts. Such tensile stresses lead to a reduction in strength of the compacted mixtures by negating a local dissolution-reprecipitation mechanism, which strengthens the NaCl-NaCl in pure NaCl tablet. This effect is proven by experimental results from NaCl specimens diametrically loaded during storage.

Prediction of Air Entrapment in Tableting: An Approximate Solution.

An approximate solution is presented for the prediction of air entrapment during tableting. Assuming weak coupling of the deformation of the solid phase, the flow of interstitial air and a set of reasonable additional geometric assumptions, the general problem is reduced to 1 dimension. Experimental values of air permeability through tablet specimens of commonly used pharmaceutical excipients were obtained using a 3D printed test cell outfitted to a powder rheometer. Using these values, combined with a numerical solution of the governing partial differential equation, parametric studies are presented that demonstrate the importance of permeability, compaction speed, tablet size, and punch-die tolerance on air entrapment. In addition, a first-order approximation of the role of entrapped air on the measured radial tensile strength of formed tablets is presented.

A Simplified Model of Moisture Transport in Hydrophilic Porous Media With Applications to Pharmaceutical Tablets.

This work establishes a predictive model that explicitly recognizes microstructural parameters in the description of the overall mass uptake and local gradients of moisture into tablets. Model equations were formulated based on local tablet geometry to describe the transient uptake of moisture. An analytical solution to a simplified set of model equations was solved to predict the overall mass uptake and moisture gradients with the tablets. The analytical solution takes into account individual diffusion mechanisms in different scales of porosity and diffusion into the solid phase. The time constant of mass uptake was found to be a function of several key material properties, such as tablet relative density, pore tortuosity, and equilibrium moisture content of the material. The predictions of the model are in excellent agreement with experimental results for microcrystalline cellulose tablets without the need for parameter fitting. The model presented provides a new method to analyze the transient uptake of moisture into hydrophilic materials with the knowledge of only a few fundamental material and microstructural parameters. In addition, the model allows for quick and insightful predictions of moisture diffusion for a variety of practical applications including pharmaceutical tablets, porous polymer systems, or cementitious materials.

An ice-templated, linearly aligned chitosan-alginate scaffold for neural tissue engineering.

Several strategies have been investigated to enhance axonal regeneration after spinal cord injury, however, the resulting growth can be random and disorganized. Bioengineered scaffolds provide a physical substrate for guidance of regenerating axons towards their targets, and can be produced by freeze casting. This technique involves the controlled directional solidification of an aqueous solution or suspension, resulting in a linearly aligned porous structure caused by ice templating. In this study, freeze casting was used to fabricate porous chitosan-alginate (C/A) scaffolds with longitudinally oriented channels. Chick dorsal root ganglia explants adhered to and extended neurites through the scaffold in parallel alignment with the channel direction. Surface adsorption of a polycation and laminin promoted significantly longer neurite growth than the uncoated scaffold (poly-L-ornithine + Laminin = 793.2 ± 187.2 µm; poly-L-lysine + Laminin = 768.7 ± 241.2 µm; uncoated scaffold = 22.52 ± 50.14 µm) (P < 0.001). The elastic modulus of the hydrated scaffold was determined to be 5.08 ± 0.61 kPa, comparable to reported spinal cord values. The present data suggested that this C/A scaffold is a promising candidate for use as a nerve guidance scaffold, because of its ability to support neuronal attachment and the linearly aligned growth of DRG neurites.

Effects of aging and degeneration on the human intervertebral disc during the diurnal cycle: a finite element study.

A significant biochemical change that takes place in intervertebral disc degeneration is the loss of proteoglycans in the nucleus pulposus. Proteoglycans attract fluid, which works to reduce mechanical stresses in the solid matrix of the nucleus and provide a hydrostatic pressure to the annulus fibrosus, whose fibrous nature accommodates this stress. Our goals are to develop an osmo-poroelastic finite element model to study the relationship between proteoglycan content and the stress distribution within the disc and to analyze the effects of degeneration on the disc's diurnal mechanical response. Stress in the annulus increased with degeneration from ∼0.2 to 0.4 MPa, and an increase occurred in the center of the nucleus from 1.2 to 1.6 MPa. The osmotic pressure in the central nucleus region decreased the most with degeneration, from ∼0.42 to ∼0.1 MPa in a severely dehydrated disc. A 3% decrease in diurnal fluid lost with degeneration equated to ∼21% decrease in fluid exchange, and hence a decrease in nutrients that require convection to enter the disc. We quantified the increases in internal stresses in the nucleus and annulus throughout the various stages of degeneration, suggesting that these changes lead to further remodeling of the tissue.

Temperature evolution during compaction of pharmaceutical powders.

A numerical approach to the prediction of temperature evolution in tablet compaction is presented here. It is based on a coupled thermomechanical finite element analysis and a calibrated Drucker-Prager Cap model. This approach is capable of predicting transient temperatures during compaction, which cannot be assessed by experimental techniques due to inherent test limitations. Model predictions are validated with infrared (IR) temperature measurements of the top tablet surface after ejection and match well with experiments. The dependence of temperature fields on speed and degree of compaction are naturally captured. The estimated transient temperatures are maximum at the end of compaction at the center of the tablet and close to the die wall next to the powder/die interface.