High Energy Ordered Mixture for Improving the Dissolution Rate of Sparingly Soluble Compounds

Bioavailability of a sparingly soluble drug is often limited by the rate of dissolution of the drug substance. The drug in a micronized form is generally employed to maximize the bioavailability. However, the micronized drugs tend to agglomerates and do not always exhibit an improved dissolution rate. In this study, a simple processing using a high energy mill was demonstrated as an effective means to utilize the entire surface area available for drug release of the micronized drug. An experimental hydrophobic drug in a micronized form was milled with a carrier, hydrous lactose using Micropulverizer to achieve a uniform mixture so-called “high energy ordered mixture”. The high energy ordered mixture provided a contact surface area taking part in dissolution 4-fold greater than the micronized drug agglomerates. Therefore, the dissolution was significantly improved, irrespective of test parameters such as agitation and the presence of surfactant. This high energy ordered mixture provided the advantages over a simple ordered mixture for: (i) complete deaggregation of the micronized drug to fine primary particles, (ii) improving the efficiency of the carrier by increasing contact surface area, and (iii) enhancing the bonding effect between the drug and lactose particles due to free water molecules released from the crystal lattices of hydrous lactose during milling. This procedure could be applied to overcome dissolution problems of sparingly soluble drugs with cohesive nature.     

High Energy Ordered Mixture for Improving the Dissolution Rate of Sparingly Soluble Compounds

Abstract

Bioavailability of a sparingly soluble drug is often limited by the rate of dissolution of the drug substance. The drug in a micronized form is generally employed to maximize the bioavailability. However, the micronized drugs tend to agglomerates and do not always exhibit an improved dissolution rate. In this study, a simple processing using a high energy mill was demonstrated as an effective means to utilize the entire surface area available for drug release of the micronized drug. An experimental hydrophobic drug in a micronized form was milled with a carrier, hydrous lactose using Micropulverizer to achieve a uniform mixture so-called “high energy ordered mixture”. The high energy ordered mixture provided a contact surface area taking part in dissolution 4-fold greater than the micronized drug agglomerates. Therefore, the dissolution was significantly improved, irrespective of test parameters such as agitation and the presence of surfactant. This high energy ordered mixture provided the advantages over a simple ordered mixture for: (i) complete deaggregation of the micronized drug to fine primary particles, (ii) improving the efficiency of the carrier by increasing contact surface area, and (iii) enhancing the bonding effect between the drug and lactose particles due to free water molecules released from the crystal lattices of hydrous lactose during milling. This procedure could be applied to overcome dissolution problems of sparingly soluble drugs with cohesive nature.     

Polydisperse powder mixtures: effect of particle size and shape on mixture stability

The effect of the shape and size of the components on the stability of mixtures was evaluated in binary mixtures of drug and carrier. Aspirin was used as model drug; spray-dried lactose and microcrystalline cellulose were used as carriers. The coefficient of variation (CV) of the drug in the mixture at various time intervals during mixing was used as a measure of homogeneity. The stability of mixtures was assessed under conditions that were conducive to segregation—in this case, prolonged mixing. The pattern of change in CV with time was analyzed in terms of convective, shear, and diffusive mixing stages. The variation resulting from a change in the shape of the carriers was smaller than that resulting from size differences. The segregation rate constant, calculated on the assumption of a first-order mixing process, was found to be larger in mixtures having components of different shape than in mixtures having components of similar shape. In mixtures of micronized drug and carrier, the pattern of change in the CV of drug with mixing time was attributed to the distribution of agglomerates of micronized drug during convective mixing, followed by shearing of agglomerates and, finally, the distribution of the primary particles during diffusive mixing. Mixtures of non-cohesive powders of similar size and shape behaved like random mixtures of non-interacting components.     

Polydisperse Powder Mixtures: Effect of Particle Size and Shape on Mixture Stability

ABSTRACT

The effect of the shape and size of the components on the stability of mixtures was evaluated in binary mixtures of drug and carrier. Aspirin was used as model drug; spray-dried lactose and microcrystalline cellulose were used as carriers. The coefficient of variation (CV) of the drug in the mixture at various time intervals during mixing was used as a measure of homogeneity. The stability of mixtures was assessed under conditions that were conducive to segregation—in this case, prolonged mixing. The pattern of change in CV with time was analyzed in terms of convective, shear, and diffusive mixing stages. The variation resulting from a change in the shape of the carriers was smaller than that resulting from size differences. The segregation rate constant, calculated on the assumption of a first-order mixing process, was found to be larger in mixtures having components of different shape than in mixtures having components of similar shape. In mixtures of micronized drug and carrier, the pattern of change in the CV of drug with mixing time was attributed to the distribution of agglomerates of micronized drug during convective mixing, followed by shearing of agglomerates and, finally, the distribution of the primary particles during diffusive mixing. Mixtures of non-cohesive powders of similar size and shape behaved like random mixtures of non-interacting components.     

Comparison of directly compressed vitamin B12 tablets prepared from micronized rotary-spun microfibers and cast films

Fiber-based dosage forms are potential alternatives of conventional dosage forms from the point of the improved extent and rate of drug dissolution. Rotary-spun polymer fibers and cast films were prepared and micronized in order to direct compress after homogenization with tabletting excipients. Particle size distribution of powder mixtures of micronized fibers and films homogenized with tabletting excipients were determined by laser scattering particle size distribution analyzer. Powder rheological behavior of the mixtures containing micronized fibers and cast films was also compared. Positron annihilation lifetime spectroscopy was applied for the microstructural characterization of micronized fibers and films. The water-soluble vitamin B₁₂ release from the compressed tablets was determined. It was confirmed that the rotary spinning method resulted in homogeneous supramolecularly ordered powder mixture, which was successfully compressed after homogenization with conventional tabletting excipients. The obtained directly compressed tablets showed uniform drug release of low variations. The results highlight the novel application of micronized rotary-spun fibers as intermediate for further processing reserving the original favorable powder characteristics of fibrous systems.     

Electro-magnetic collapse of thick-walled cylinders to investigate spontaneous shear localization

We present an electro-magnetic (EM) setup in order to collapse thick-walled cylinders, for the investigation of spontaneous formation of multiple adiabatic shear bands. The EM setup is based on a pulsed current generator using a capacitor bank system. The cylindrical specimen is part of an assembly of coaxial cylinders, where the inner and outer cylinders, each attached to an opposite pole, are short-circuited. Upon capacitor discharge, a high current flows through the cylinders, in opposite directions, creating repulsive magnetic forces between them. The outer cylinder is driven outwards and the inner cylinder is driven inwards - in a collapsing manner. This work presents the design procedure of the specimens’ geometry using numerical simulations, and some preliminary experimental results for SS304L steel specimens. The spatial distribution of the multiple adiabatic shear bands in these specimens is in good agreement with that reported in the literature for explosively driven experiments with the same material. Our numerical simulations of the collapsing cylinder show good agreement with the experimental results for both global behavior and shear band distribution.     

Experimental investigations on buckling of cylindrical shells under axial compression and transverse shear

This paper presents experimental studies on buckling of cylindrical shell models under axial and transverse shear loads. Tests are carried out using an experimental facility specially designed, fabricated and installed, with provision forin-situ measurement of the initial geometric imperfections. The shell models are made by rolling and seam welding process and hence are expected to have imperfections more or less of a kind similar to that of real shell structures. The present work thus differs from most of the earlier investigations. The measured maximum imperfections δ_max are of the order of ±3t (t = thickness). The buckling loads obtained experimentally are compared with the numerical buckling values obtained through finite element method (FEM). In the case of axial buckling, the imperfect geometry is obtained in four ways and in the case of transverse shear buckling, the FE modelling of imperfect geometry is done in two ways. The initial geometric imperfections affect the load carrying capacity. The load reduction is considerable in the case of axial compression and is marginal in the case of transverse shear buckling. Comparisons between experimental buckling loads under axial compression, reveal that the extent of imperfection, rather than its maximum value, in a specimen influences the failure load. Buckling tests under transverse shear are conducted with and without axial constraints. While differences in experimental loads are seen to exist between the two conditions, the numerical values are almost equal. The buckling modes are different, and the experimentally observed and numerically predicted values are in complete disagreement.     

Micronization of sulfamethoxazole using the supercritical anti-solvent process

Micronization of an antibiotic compound sulfamethoxazole was investigated in this study using the supercritical anti-solvent (SAS) precipitation method. The results from either the batch or continuous process were compared, and the latter one yielded smaller particles. Effects on particle size due to various process parameters in the continuous SAS process (the concentration and the flow rate of the solution of sulfamethoxazole, the operating pressure and temperature) had been studied through a fractional factorial design for sulfamethoxazole. The experimental results showed that there was a significant interaction between the parameters of the flow rate and the concentration of the sulfamethoxazole solution. Analyses of the micronized sulfamethoxazole particles were examined using SEM, XRD and DSC. Sulfamethoxazole was micronized from its original size of 41.7 to 5.1 μm. The micronized sulfamethoxazole exhibited a higher dissolution rate in a simulated intestinal fluid than that of the original compound. It was further demonstrated that the co-precipitation of sulfamethoxazole with a hydrophilic polymer hydroxypropyl cellulose (HPC) in the continuous SAS process provided more enhanced dissolution rate.     

Influence of Magnesium Stearate on the Homogeneity of a Prednisone-Granule Ordered Mix

The use of ordered systems has been advocated in the formulation of microdose delivery systems to improve and maintain drug homogeneity during mixing. This study considered the effect of a lubricant such as magnesium stearate on the degree of homogeneity and stability of a preformed prednisone-granule ordered mix. Micronized prednisone was mixed with starch-lactose granules to produce an ordered mix of satisfactory homogeneity. Magnesium stearate in concentrations above and below the theoretical surface saturation of the granule caused negligible change in the degree of homogeneity. Sieve analysis of the mix and subsequent analysis of size fractions for prednisone allowed the prednisone distribution within the mix to be determined. Prednisone was found to be associated with the granules in all the mixes; the magnesium stearate did not compete for the surface adsorption sites and did not dislodge the drug from the granule surface, during mixing and mild demixing conditions. However, a decrease in surface adsorbed prednisone occurred in all mixes (with and without magnesium stearate) under more severe segregating conditions.

Recent research in drug homogeneity studies in microdose tablets has highlighted serious problems in dosage variation¹. Drugs are frequently micronized to improve their release from the solid dosage form. Micronization produces drug particles which are extremely cohesive and interactive. In practice, the adequate mixing of micronized powders with other excipients may be difficult to achieve since this cohesiveness produces aggregation of drug particles and interaction of the drug with the mixer surfaces. In recent years some research effort has been applied to using the interactive nature of drug particles to improve the homogeneity of mixes^2,3. Controlled adsorption of a micronized drug particle onto a carrier particle to produce an “ordered unit” has been shown to minimize segregation within the mix^4,5. Some of the factors affecting the degree of homogeneity of “ordered mixes” have been studied^6,7. However, little research has been conducted on the influence of other excipients on the homogeneity and stability of preformed ordered mixes. A cautionary note on the use of magnesium stearate in ordered mixtures indicated that the lubricant may displace salicylic acid from a sucrose carrier under conditions of segregation⁸. The purpose of this study, therefore, was to evaluate the influence of a third component such as magnesium stearate on the degree of homogeneity and stability of a preformed prednisone-starch lactose granule ordered system during a mixing process.     

Flowability of binary mixtures of commercial and reprocessed ibuprofen through high shear wet milling (HSWM) with lactose

This study investigates the flow properties of binary mixtures of both commercial ibuprofen and reprocessed ibuprofen through high shear milling with lactose powders. Ibuprofen is recrystallized in a 30% water–ethanol mixture before high shear wet milling (HSWM). In-situ Process Analytical Techniques (PAT) (Labmax®) is used to study the HSWM process dynamics, with particle size measured by a Lasentec Focused Beam Reflectance Measurement, FBRM®. The flow properties of the binary mixtures of the different ibuprofen particles and its binary mixtures with lactose were measured using a Schulze® RST-XS ring shear tester. Results show that the morphology of ibuprofen was changed from needle to hexagonal like crystals during recrystallization and crystal size was reduced dramatically by HSWM for 1 h. The flowability of milled ibuprofen powders is reduced significantly due to its reduced size and change of surface morphology. Mixing the HSWM ibuprofen powders with lactose enhanced its flow properties. However, the increase of the mixture flowability for HSWM ibuprofen is less significant in comparison to the binary mixtures of lactose with commercial ibuprofen.     

Computer simulations of domain growth in off-critical quenches of two-dimensional binary mixtures

The phase separation of two-dimensional binary mixtures has been studied through numerical Langevin simulations based on a Ginzburg–Landau free energy. We have considered not symmetric mixtures with and without imposed shear flow. In the sheared case our main results are as follows: (1) domains are distorted by the flow; (2) the structure factor has four peaks; (3) excess viscosity shows a peak whose position is independent of shear rate but its height decreases increasing shear rate.     

Superfluid Helium Between Rotating Cylinders

The isotopic ordering of H2–D2 mixtures adsorbed at low temperature on graphite in the monolayer range is measured by small angle neutron scattering (SANS). We show that below 8 K, solid mixtures exhibit isotopic clustering at large density (monolayer completion) and a tendency towards the formation of ordered compounds for smaller density (near the commensurate structure).     

Dissolution and Uniformity Properties of Ordered Mixes of Micronized Griseofulvin and A Directly Compressible Excipient

Ordered mixes of micronized griseofulvin were prepared with a commercially available directly compressible excipient. The excipient consisted of a combination of maltose and dextrose and a particle size fraction of approximately 250-850µ was employed in the mixing studies. Ordered mixes containing 0.25%, 0.5%, and 1% active ingredient were prepared and after thirty minutes of mixing, excellent content uniformity of the mixes was seen. Rapid dissolution of drug from the sugar granules was observed when the drug coated granules were tested using the U.S.P. Paddle Method. The ordered mixing process provided an even coat of the micronized drug onto the granules. As the granules dissolved, particle-particle interactions and aggregation problems with the hydrophobic drug were eliminated. The properties of griseofulvin tablets prepared from these ordered mixes were evaluated and the tablets showed excellent content uniformity and rapid dissolution of griseofulvin from the dosage form.     

Dissolution and Uniformity Properties of Ordered Mixes of Micronized Griseofulvin and A Directly Compressible Excipient

Abstract

Ordered mixes of micronized griseofulvin were prepared with a commercially available directly compressible excipient. The excipient consisted of a combination of maltose and dextrose and a particle size fraction of approximately 250-850µ was employed in the mixing studies. Ordered mixes containing 0.25%, 0.5%, and 1% active ingredient were prepared and after thirty minutes of mixing, excellent content uniformity of the mixes was seen. Rapid dissolution of drug from the sugar granules was observed when the drug coated granules were tested using the U.S.P. Paddle Method. The ordered mixing process provided an even coat of the micronized drug onto the granules. As the granules dissolved, particle-particle interactions and aggregation problems with the hydrophobic drug were eliminated. The properties of griseofulvin tablets prepared from these ordered mixes were evaluated and the tablets showed excellent content uniformity and rapid dissolution of griseofulvin from the dosage form.     

A micromechanical model for kink-band formation: Part I — Experimental study and numerical modelling

The initiation and propagation of kink-bands are investigated through an experimental study and numerical modelling. Based on the results achieved, the sequence of events and key features for kink-band formation are identified; particularly, matrix yielding is found to play a crucial role in the process, and fibres are found to fail in the compressive side first. The findings from both the experimental and numerical programmes show a remarkable agreement, and are further applied to the development of an analytical model (Part II of this paper) for kink-band formation.     

Study on Failure Characteristic of Rock‐Like Materials With an Open‐Hole Under Uniaxial Compression

Abstract: The failure strength model of brittle materials with a pre‐existing open‐hole defect is proposed in this paper. A modified Sammis–Ashby model is deduced, in which it can be used to calculate the peak strength of brittle materials. It shows the law between peak strength σ_p and independent variable μ, which is the ratio of open‐hole radius (a) to half‐width of the specimen (t). Moreover, numerical and experimental investigations on failure process of rock‐like materials with an open‐hole imperfection were carried out. In the experiments, 3D‐digital image correlation method, an optical technique which utilises the full‐field and non‐contact measurement, was employed. A progressive elastic damage method realistic failure process analysis (RFPA) was used in the numerical investigation to inspect and verify the modified model and simulate the failure process. The investigation finds that there are good correlations between the experimental, numerical and theoretical results. Moreover, because of the influences of boundary conditions, shear failure type was obtained both experimentally and numerically.     

Shear coefficient determination in linear friction welding of aluminum alloys

In the present study, a combined experimental and numerical investigation on Linear Friction Welding (LFW) of AA2011-T3 aluminum alloy was carried out in order to find the temperature dependent shear coefficient to be used in a 3D numerical model of the process. Torque, oscillation frequency and pressure were acquired in order to calculate the shear stress at the interface. A numerical thermal model was used to calculate the temperature at the interface between the specimens starting from experimental temperatures acquired through a thermocouple embedded in the LFW specimens. Finally, the calculated shear coefficient was used to model the contact between the two specimens in a dedicated 3D, Lagrangian, thermo-mechanically coupled rigid-viscoplastic numerical model of the LFW process. A narrow range of variation of the shear factor vs temperature curve was found with varying LFW process parameters and good agreement was obtained for the temperature prediction of the 3D model of the process.     

Effective anisotropic elastic constants of bimaterial interphases: comparison between experimental and analytical techniques

The effective elastic constants of a bimaterial composite were experimentally measured with the goal of validating the numerical predications of these constants made by homogenization theory. Secondly, solutions predicted by homogenization theory were compared to predictions made with more standard composite theories. Composite specimens consisting of titanium and epoxy were developed to mimic a porous titanium/tissue interphase. Tensile and shear tests (ASTM D3983) measured the stiffness along the porous coating/epoxy interphase (E _L), across the interphase (E _T) and in shear (G _LT). No significant differences in moduli were found between the experimental measurements and predictions made with homogenization theory, nor between the experimental measurements and Hashin-Shtrikman estimates. Homogenization theory predicted results usually within 20% of Hashin-Shtrikman estimates, but typically more than 50% different from what is predicted by the rule of mixtures. However, homogenization theory allows calculation of anisotropic stiffness estimates and local strains, neither of which is possible using Hashin-Shtrikman estimates. With this experimental validation, the accuracy of homogenization theory for use in implant/tissue interface mechanics applications is confirmed. Since the composite interphase is anisotropic and more compliant in the transverse direction, with stiffness an order of magnitude lower across the interphase, local mechanics, tissue ingrowth and remodeling may be strongly directional dependent.Department of Surgery, Orthopaedic Research LaboratoriesDepartment of Biologic and Materials Sciences, School of Dentistry     

Dynamics of particle chopping in blenders and food processors

Mathematical models are developed to explain the size distribution of particles in blenders to give insight into the behaviour of possible blender designs. The initial models consider idealized simplified situations, first with the chopping of long thin particles and then of spheres. The models are first presented using the idea of chopping at discrete places but then extended to account for chopping at any point via a continuous model. Some of the simple models can be solved analytically while others require numerical calculations. Comparisons of the predictions from the various models with experimental data at a fixed time are presented and show that the models account for much of the behaviour. The initial models do not however predict the large amount of extremely small particles (debris) that are observed at the end of the blending process. The models are thus modified using simple extensions to account for additional effects and numerical solutions of these models are compared with the observed data. The theory should provide a useful tool that eliminates the need to perform costly and time-consuming experiments when understanding how a particular food will be blended.     

Micronized plastic waste recycling using two-disc tribo-electrostatic separation process

Triboelectrostatic separation of millimeter-size granular mixtures is nowadays widely used in the recycling industry. However, the separation of micronized particles of an average granulometric size of 100?µm is still inefficient. This paper is aimed to carry out an experimental investigation of a triboelectrostatic separation process based on a fluidized bed tribocharging system produced between a pair of rotating aluminum disks supplied by two high-voltage DC supplies of opposite polarities. The granular mixture used in this work is composed of micronized white pure virgin PolyVinyl Chloride particles (WPVC) and gray PolyVinyl Chloride particles that contain a small percentage of carbon (GPVC) of average size 100?μm. Moreover, a homemade method was developed to estimate the purity of the separated products. It was deduced that the separation outcome, in terms of recovery and purity, is efficient and depends on several factors: the high-voltage level, the rotating speed of the disks, the fluidization rate, the total mass of the fluidized bed and the composition ratio of the granular mixture.