Investigation and modelling approach of the mechanical properties of compacts made with binary mixtures of pharmaceutical excipients.

Three pharmaceutical excipients (microcrystalline cellulose, lactose, anhydrous calcium phosphate) and their binary mixtures were compacted to form compacts of various mean porosities. Some mechanical properties (Young's modulus, tensile strength and Brinell hardness) were studied on these compacts. The mechanical properties of the binary mixtures were not proportional to the mixture composition expressed in mass. More, for all the properties, a negative deviation was always observed from this linear relationship. In reference to a composition percolation phenomenon, critical mass fractions were detected from the graph mechanical property vs. mass composition of a mixture. The results obtained with Brinell hardness differed from the results of the Young's modulus and the tensile strength, i.e. the most plastic material in the binary mixture controlled the mixture behaviour. Secondly, a predictive model based on a statistical approach was proposed for the Young's modulus and the tensile strength. The validity of this model was verified on experimental data, and an interaction parameter used to characterize the affinity of the two compounds was calculated. Finally, the X-ray tomography technique was applied to the compacts of cellulose/phosphate mixtures to obtain cross-sections images of the compacts. The analysis of the cross-sections images allowed explaining the no linear relationship of the different mechanical properties results observed on these binary mixtures.

Compaction behaviour and new predictive approach to the compressibility of binary mixtures of pharmaceutical excipients.

The compressibility of three pharmaceutical excipients (microcrystalline cellulose, lactose and anhydrous calcium phosphate) and their binary mixtures was studied. The aim of this work was to observe the impact of the mass composition of the mixture on the compressibility. The single-compound materials and their mixtures were compacted using instrumented presses. It allowed obtaining compression cycles (i.e., force-displacement curves) which were associated with energy measurements (specific compaction energy, Esp cp and specific expansion energy, Esp exp). It was observed that for the mixtures studied, the change of Esp cp with the mass composition could be fitted using a linear relationship (it was not the case with Esp exp). A linear relationship between the porosity of mixture's compacts and the mass composition was also obtained. Heckel's plots were then obtained for the three excipients and the mixtures. The mean yield pressure was calculated with the "in-die-method" and the "out-of-die method". A proportional relationship was not valid for the mean yield pressures. But, a predictive approach was proposed in order to obtain indirectly the mean yield pressure of a binary mixture if the data of the single materials were known. It used the linear mixing rule observed with the porosity. The validity was verified and compared with the experimental values. This comparison showed that it was possible to predict the mean yield pressure of binary mixtures from the accessible data of the single excipients.

Nematic ordering of suspension of charged anisotropic colloids detected by multinuclear quadrupolar spectra and 1H PGSE-NMR measurements.

The structure of aqueous dispersion of charged anisotropic nano-composites (synthetic Laponite clays) have been studied by NMR and numerical simulations based on a multi-scale statistical analysis have been used to interpret the mobility of the confined water molecule diffusing within dense Laponite aqueous dispersions (29-52% w/w) prepared by uniaxial compression. Firstly, the lineshape detected by NMR quadrupolar spectroscopy of the counterions ((23)Na or (7)Li) exhibits a large residual splitting Delta nu which is the fingerprint of the macroscopic nematic ordering of the anisotropic particles. Secondly, these results are also confirmed by the anisotropy of the self-diffusion tensor of the water molecule measured by (1)H Pulsed Gradient Spin Echo NMR. This self-diffusion anisotropy increases with the suspension density. Thirdly, the multi-scale statistical analysis of the water mobility bridges the gap between the time-scale (ps) accessible by Molecular Dynamics simulations and the time-scale (micros) accessible by Brownian Dynamics, leading to macroscopic behaviour comparable with PGSE-NMR data measurements.

Characterization of porous structure through the dynamical properties of ions confined in sulfonated polyimide ionomers films.

The structure of sulfonated PolyImide (sPI) ionomer membrane has been investigated via the transport properties of ions confined inside. Transport coefficients of N(CH(3))(4)(+) and Na(+) ions have been determined by several techniques in order to get a range of time/space scale as wide as possible: a method using radiotracers, conductivity, pulsed field gradient NMR and NMR quadrupolar relaxation rates determination. For N(CH(3))(4)(+), the self-diffusion has been measured in the direction of membrane plan (parallel) and in the perpendicular direction (transverse), whereas for Na(+) only transverse self-diffusion has been measured. The conductivity of both ions has been measured in the transverse direction. The results show a anisotropic and multiscale structure with a separation phase between hydrophilic and hydrophobic domains that is not well-defined.

Anisotropy of the solvent self-diffusion tensor as a probe of nematic ordering within dispersions of nanocomposites.

The anisotropy of the solvent self-diffusion coefficient within suspensions of nanoparticles is measured by (1)H nuclear magnetic resonance with pulsed field gradient and used as a new procedure to detect nematic ordering. The potentiality of this method is illustrated using aqueous clay dispersions whose nematic ordering was already detected by (23)Na quadrupolar splitting.

Magnetic resonance imaging investigation of the mixing-segregation process in a pharmaceutical blender.

Magnetic Resonance Imaging (MRI) was used to study the mixing process of binary mixtures of free flowing sugar beads in a Turbula mixer. In order to make particles MRI-sensitive, some reference beads were doped with an organic oil. Doped and undoped particles were mixed and MRI was used to non-destructively image the particle bed for a given number of mixer rotations (NR), bead diameter ratio (R=d(ref)/d(i)) and rotation speed (V). All the results were quantified on the basis of image analysis to characterise the degree of mixing. Studies showed that for binary mixtures of identical particle size, the mixing was complete after 30 rotations, whereas for beads of different size (R=2.8) a segregated steady state was obtained after nearly 10 rotations. Experiments revealed that segregation appeared as soon as R=0.9. Moreover, the lower the rotation speed, the more segregated the final state was. It appeared that for a filling level greater than 80%, dead regions appeared in the centre of the powder bed. In conclusion, when the particles are non-cohesive, the Turbula blender perfectly mixes identical beads but segregation occurs for beads of different size after just a few rotations.

A new method for three-dimensional skeleton graph analysis of porous media: application to trabecular bone microarchitecture.

This paper introduces a new three-dimensional analysis of complex disordered porous media. Skeleton graph analysis is described and applied to trabecular bone images obtained by high resolution magnetic resonance imaging. This technique was developed bearing in mind topological considerations. The correspondence between vertices and branches of the skeleton graph and trabeculae is used in order to get local information on trabecular bone microarchitecture. In addition to real topological parameters, local structural information about trabeculae, such as length and volume distributions, are obtained. This method is applied to two sets of samples: six osteoporosis and six osteoarthritis bone samples. We demonstrate that skeleton graph analysis is a powerful technique to describe trabecular bone microarchitecture.

Fractal dimension of trabecular bone projection texture is related to three-dimensional microarchitecture.

The purpose of this work was to understand how fractal dimension of two-dimensional (2D) trabecular bone projection images could be related to three-dimensional (3D) trabecular bone properties such as porosity or connectivity. Two alteration processes were applied to trabecular bone images obtained by magnetic resonance imaging: a trabeculae dilation process and a trabeculae removal process. The trabeculae dilation process was applied from the 3D skeleton graph to the 3D initial structure with constant connectivity. The trabeculae removal process was applied from the initial structure to an altered structure having 99% of porosity, in which both porosity and connectivity were modified during this second process. Gray-level projection images of each of the altered structures were simply obtained by summation of voxels, and fractal dimension (Df) was calculated. Porosity (phi) and connectivity per unit volume (Cv) were calculated from the 3D structure. Significant relationships were found between Df, phi, and Cv. Df values increased when porosity increased (dilation and removal processes) and when connectivity decreased (only removal process). These variations were in accordance with all previous clinical studies, suggesting that fractal evaluation of trabecular bone projection has real meaning in terms of porosity and connectivity of the 3D architecture. Furthermore, there was a statistically significant linear dependence between Df and Cv when phi remained constant. Porosity is directly related to bone mineral density and fractal dimension can be easily evaluated in clinical routine. These two parameters could be associated to evaluate the connectivity of the structure.

A NMR investigation of adsorption/desorption hysteresis in porous silica gels.

The purpose of this study is to investigate possible differences in geometry and connectivity of the liquid phase in a partially water-satured porous medium between the adsorption and the desorption branches, using a series of silica gels. This was done by comparing the T1 and T2 relaxation times (in 1H and 2H nuclear magnetic resonance (NMR) relaxation) as well as the water self-diffusion coefficient D (in 1H) along the two branches of the adsorption/desorption isotherms. The results show that the two relaxation times and the diffusion coefficient are strongly dependent on the water content (saturation level). When plotted in normalized coordinates, the T1 and T2 vs. P/Po curves fit closely the adsorption/desorption isotherms, which validates the two-population, fast-exchange model. Furthermore, because at equivalent saturation levels, there is no difference between the relaxation times and diffusion coefficients obtained along the adsorption branch and those obtained along the desorption branch, one is led to the conclusion that despite different equilibrium conditions, the geometry and connectivity of the liquid phase are statistically the same along the two branches.

Analysis of the Multilayer Thickness Relationship for Water Vapor and Nitrogen Adsorption.

Six silica gels, where each gel had a characteristic calibrated pore size (40-4000 Å), have been characterized both by water vapor and nitrogen adsorption isotherms. From these results, it was concluded that two-thirds of the silica surface is hydrophobic. The selection of wide pores (>300 Å) has enabled the determination of both the water and nitrogen t-curves for porous silica. It was observed that the development of the multilayer was identical in the wide pores irrespective of their size between 300 and 4000 Å. The porous silica t-curve for water coincided exactly with the t-curve of nonporous adsorbents provided that their BET C constants were similar. For nitrogen t-curves, a matching BET C constant ensured similarity only in the monolayer region, above which divergence progressively increased, becoming important close to saturation. The effect of the t-curve choice on the pore size distribution was established. A t-curve displaying reduced adsorption had a tendency to shift the pore-size distribution to lower dimensions, toward the micropore region. As a consequence, the cumulated surface area obtained from the BJH model gave increasingly higher values than the BET nitrogen surface area. However, the pore-size distribution was shifted to higher pore sizes when the selected t-curve was above the natural t-curve. Errors as much as 25% were detected for the mean pore radius and cumulated surface area for certain literature t-curves. A comparison of the water and the nitrogen t-curves indicated a crossover point when the water multilayer thickness became greater than the nitrogen thickness. Such behavior lends support to the cooperative adsorption mechanism for water vapor once a fixed number of water molecules (two layers) are present on the surface. Copyright 1998 Academic Press.