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The bulk properties of a powder are dependent on the preparation, treatment, and storage of the sample, that is, how it was handled. The particles can be packed to have a range of bulk densities and, moreover, the slightest disturbance of the powder bed may result in a changed bulk density. Thus, the bulk density of a powder is often difficult to measure with good reproducibility and, in reporting the results, it is essential to specify how the determination was made. In this article, we measured the bulk density, tapped density, and calculated the Hausner ratio of commonly used excipients with similar tapped density testers and followed the United States Pharmacopeia 30-National Formulary 25-S1 testing procedure. Based on the analysis, within lot and lot-to-lot variability and the relative errors for bulk density, tapped density, and Hausner ratio were found to be acceptable. Lot-to-lot differences were generally not measurable using this test as they were found to be within the variability of the test. The results also indicated that there was no statistically significant bias between sites for tapped density and Hausner ratio, but there was a marginally significant bias in the bulk density data set.

The mechanical behavior of powders during die compaction was investigated using the discrete element method (DEM), in which powders are modeled as discrete particles with elastoplastic material behavior. A new adhesive elastoplastic contact model that describes the force displacement behavior of contacting particles subjected to high confining conditions was introduced and implemented in DEM simulations of die compaction and uniaxial tension. The objectives of these simulations were: (1) to investigate the micromechanical behaviors of powder systems during die compaction; (2) to understand the influence of model parameters on the macroscopic behavior; and (3) to develop a methodology for the calibration of the model parameters from macroscopic experimental results. The methodology developed for the calibration of the model parameters was carried out by a combination of statistical design of experiments (DOE) and optimization techniques. The calibration methodology provided simulation results that were in good agreement with experimental results conducted on hot melt extruded (HME) copovidone powder. One of the key advantages of the calibration procedure is the need for only two experimental techniques – die compaction, and diametric compression strength tests. Furthermore, examination of the microscale behavior from simulated results revealed a connection between the level of interparticle cohesion and the corresponding level of residual wall stress of powder compacts after complete unloading in die compaction. It was found that lower levels of interparticle cohesion resulted in decreased residual wall stresses and an increase in the axial spring back from the minimum compact height at the end of compaction. These results suggest that the decrease in residual wall stress and the increase in axial spring back with lower levels of interparticle cohesion depend not only on the elastic properties of the constituent particles during unloading, but also depend on the decohesion of particle-particle contacts.

In order to improve fundamental understanding of powder flow behavior which is essential to the success of many pharmaceutical processes, this study investigates the relationship between particle-scale interactions dominated by the cohesive van der Waals force and the flow function coefficient. This study finds that the granular Bond number, defined as the ratio of the inter-particle cohesion force to particle weight, correlates well to the flow function coefficient, a metric used to assess powder flow performance and defined as the ratio of consolidation stress to unconfined yield strength. The inter-particle cohesion force was calculated by the so-called multi-asperity model which is a modification of the well-known Rumpf equation. As a major novelty, a granular Bond number is defined for multi-component mixtures (i.e. powder blends) and used to predict the flow function coefficient of binary, ternary, and quinary mixtures of a model API, acetaminophen, and two common pharmaceutical excipients, microcrystalline cellulose and pregelatinized starch. Surface modification via dry-coating was also used to alter the inter-particle force and more thoroughly investigate the effect of particle interactions on powder flow performance. Since the multi-component granular Bond number takes into account particle properties and particle interactions of all components in the powder blend, this novel approach shows good predictability for powder mixtures. Although the flow function coefficient alone is not a stringent prediction of powder flow, the modeling effort put forth in this study can be used to better guide formulation development.

The present study explores new approaches to extract Drucker–Prager/Cap (DPC) constitutive model parameters at low and high densities of compacted powders for which it is not possible to get solid, undamaged samples for model calibration purposes. Extrapolations were carried out by invoking a number of physically plausible assumptions for high density conditions and the addition of the experimental shear cell testing procedure for low density extrapolations. The effects of these extrapolations on finite element model (FEM) results of both die compaction and roller compaction were examined. The sensitivity of the extrapolated DPC parameters on compaction model results was explored by performing parametric studies for both low and high density extrapolations. Examination of die compaction model results for low density showed little sensitivity to extrapolations; however, we are able to show that extrapolations of DPC parameters to low density may have a significant effect on roller compaction modeling results. High density die compaction FEM simulations reveal a significant effect on the way in which the DPC model parameters are extrapolated to high density. A method of extrapolating the DPC model parameters to high density is presented in this work. The work presented here demonstrates the significance of properly calibrating the DPC model at low and high densities and provides the necessary guidance for this purpose.

A finite element study of the interparticle force–displacement laws on contacts of spheres at conditions corresponding to compacts pressed to high relative densities is presented here. Under these conditions, the response of a contact can be affected by the presence of neighboring contacts. Finite element simulations of axisymmetric models of equispaced and equally loaded contacts show that the force–displacement law is not unique and depends on the number of neighboring contacts. The force at a given interparticle deformation is minimum for Z = 2 but at higher coordination numbers becomes larger after a critical deformation due to the interaction of the stress fields of neighboring contacts. This difference is magnified when the local porosity closes. Furthermore, numerical simulations of periodic arrays of spheres were conducted to assess the effect of loading path and the formation of new contacts on the response of existing contacts. In both cases, it was found that, the contact response depends on the overall triaxiality of the deformation of the particle. A new deformation fabric tensor is proposed based on the deformation and direction of all contacts on a particle. The first and second invariants of this tensor are used to characterize the triaxiality of the deformation on a particle. These results form the basis for more appropriate force–displacement laws at contacts that can be implemented in discrete element simulations for high density problems.

In an effort to identify the origin and the evolution of damage during the compaction/ejection cycle of powder compacts, an experimental study that compares compacts in straight and tapered dies in terms of the presence and growth of microcracks was carried out using x-ray tomography and environmental scanning electron microscopy. The results presented here document the presence of internal microcracks at high relative densities, and microcracks on the surface of the compacts. Parts compacted in tapered dies exhibit microcracks with smaller crack tip opening and have a higher axial strength than those made in a straight die. These experimental observations, together with the ideas of damage generation under compressive stresses, as well as finite element analysis of the stress field in the compact as it exits from the die, confirm the hypothesis that a two-step mechanism is responsible for damage generation in powder compacts. First, microcracking occurs during unloading within the die at high pressures and subsequently surface cracks grow under the localized stresses as the compact emerges from the die.

Drying is one of the most commonly used unit operations in the preparation of dry granules by thermally removing volatile solvent from the wet solid. The study focuses on the quantitative investigation of heat transfer in a filter dryer in the quest to determine the optimum drying conditions. Consequently, contact drying kinetics of glassbeads–ethanol and lactose–ethanol system is investigated using an agitated filter dryer (Charles Thompson). Discrete element method is employed to simulate granular flow, mixing and heat transport in the vessel. Typical system with glass beads is numerically simulated using appropriate material properties and validated by the experimental findings. A parametric study for both simulations and experiments is performed to assess the effect of various conditions of wall temperature, fill level and impeller speed on the drying performance in the filter dryer. A high wall temperature showed an increase in the drying rate and a sharp rise in the average bed temperature, thereby decreasing the total time for drying operation. An increase in fill volume (bed depth) at constant wall temperature and speed resulted in a decline in the drying rate. The rotational speed had a nominal impact on drying of glass beads. Hence low rotational speeds seemed optimal for contact drying.

The preparative-scale separation of two proteins into adjoined, pure bands was accomplished using a novel, hybrid chromatography method which employs chromatofocusing using a self-sharpening pH front and displacement development. The method eliminates the use of a traditional displacer for accomplishing displacement chromatography, and was used to separate the A and B forms of β-lactoglobulin using a strong-base anion-exchange column packing and a buffer system composed of acetic acid and either 3-(N-morpholino)propane-sulfonic acid (MOPS) or 2-(N-morpholino)ethanesulfonic acid (MES). Sample loads up to 150 mg of protein were applied to a 75×7.5 mm column to produce a displacement train composed of highly pure protein bands with greater than 90% recovery of protein. A discussion is given of the chromatographic behavior of proteins under concentration overloaded conditions for the case where a self-sharpening pH front formed using adsorbed buffering species is used to desorb proteins from an anion-exchange column packing.

Obscurin is a multidomain protein composed of adhesion and signaling domains that plays key roles in the organization of contractile and membrane structures in striated muscles. We used adenoviral-mediated gene transfer to overexpress its extreme NH2-terminus in developing myofibers, followed by immunofluorescence and ultrastructural methods to study its effects in sarcomerogenesis. We found that overexpression of obscurin's second immunoglobulin domain (Ig2) inhibits the assembly of A- and M-bands, but not Z-disks and I-bands. This effect is mediated by the direct interaction of obscurin's Ig2 with a novel isoform of the thick filament associated protein, Myosin Binding Protein-C Slow (MyBP-C slow), that corresponds to transcript variant-1. Variant-1 contains all the structural motifs known to be present in MyBP-C slow (variant-3), but has a unique COOH-terminus consisting of twenty-six amino acids and a new termination codon. RT-PCR showed that variant-1 is abundantly expressed in skeletal muscles during development and at maturity. Quantitative RT-PCR further demonstrated that transcripts containing the novel COOH-terminus are expressed in higher amounts than those lacking it. Three different antibodies to the unique COOH-terminus of variant-1 labeled M-bands and flanking regions in both developing and adult myofibers, suggesting that unlike other forms of MyBP-C that reside in C-zones, variant-1 preferentially concentrates in the middle of the A band. Adenoviral overexpression of obscurin's Ig2 domain and reduction of obscurin via siRNA inhibited the integration of variant 1 of MyBP-C slow into forming M-bands in skeletal myotubes. Collectively, our experiments identify a new ligand of obscurin at the M-band, MyBP-C slow variant-1, and suggest that its interaction with obscurin contributes to the assembly and maintenance of M- and A-bands.

The amoun t of ozone overhead in the s tratosphere varies from about I to 4 mm. when represented as a layer of pure gas reduced to normal t empera ture and pressure. Ozone present in such a small amount , compared with the other a tmospheric gases (see Table I), would not seem to be an impor tan t consti tuent . On the contrary, it is very impor tant in astrophysics, meteorology, geophysics and biology because of its absorption of ultraviolet light to produce the short wavelength limit for the spect rum of the sun and other astronomical bodies at ~ 3000 A. In a paper on atmospheric ozone, Ladenburg 1 writes, " W i t h o u t the presence of ozone in the stratosphere, life on ear th would not exist in its present form. The ultraviolet radiation from the sun exerts strong physiological effects upon every organism, as for example formation of erythems, destruct ion of bacteria, product ion of vitamins. The very shortest wavelengths of the sun have the greatest effect on the human skin. Small changes of the intensity of the sun in this region of the spectrum are biologically very (significant). These facts account for the wide interest and the general importance of the s tudy of the atmospheric ozone." The absorption which makes the atmosphere entirely opaque at wavelengths less than 2913 A is due to the Hart ley ozone band. Partial absorption by this Hart ley band extends to the Huggins bands which occupy the spectral region from 3200 to 3300 A. There is also significant ozone absorption in the visible spectrum by the Chappius bands. The Hart ley and Huggins bands have been employed by

This paper describes an approach to the practical problem of infrared atmospheric transmission.It compares and relates published data from diverse investigations. The method separates water vapor band absorption, on which there appears to be general agreement, from the less tractable continuous attenuation by fog, haze, and smoke. This separation is effected by a smooth envelope curve drawn tangent to the principal maxima in the observed transmitted spectra.In each window, the monochromatic transmission at the window peak is shown to be representative of the effect of continuous absorption on the total transmission in the window region. A simple empirical relation is developed to represent the dependence of the band absorption on the water path for each window. The dependence of continuous attenuation upon the water path for clear atmosphere is described, and the effects of haze, fog, and smoke are very briefly discussed.