P. Tchoreloff

Rheological characterization of pharmaceutical powders using tap testing, shear cell and mercury porosimeter

Most of the pharmaceutical processes involved in the manufacturing of so lid dosage forms are connected with powder flow properties, at least for some of the intermediate steps. Powder flow characteristics are commonl y investigated by various measurements, such as handling angles, tap tes ting, shear cell measurements, etc. All these approaches allow the calc ulation of indices characterising powder flowability. Unfortunately, th ese methodologies are highly product consuming, which is a limitation in the first steps of a novel drug development, when only a small amount of product is available. The use of mercury porosimetry to evaluate compre ssibility and flow properties of powders could be a new and alternative approach to obtain insight in the rheological properties of granular med ium by the interpretation of the first part of programs (low pressures) . We have developed such an evaluation and compared the results obtaine d with those given by tap testing and shear cell measurements, applied t o four excipients for direct tabletting and three different drugs. Merc ury porosimetry turned out to be a sensitive technique, able to providequantitative information about powder flow properties, complemen ted by an evaluation of particles micro porosity and size distribution, in a single step. These characterisations are obtained with only approx imately 250mg of bulk powder compared to high quantities ( >100g) needed for other methods.

Curing of aqueous polymeric film coatings: Importance of the coating level and type of plasticizer.

The aim of this study was to better understand the effects of the curing conditions on the resulting drug release patterns from pellets coated with aqueous polymer dispersions. Diltiazem HCl was used as model drug, ethylcellulose as polymer, triethyl citrate (TEC), dibutyl sebacate (DBS), and distilled acetylated monoglycerides (Myvacet) as plasticizers. Interestingly, the effects of the curing conditions strongly depended on the coating level and the type of plasticizer: in the case of TEC, the drug release rate monotonically decreased with increasing harshness of the curing conditions (time, temperature, and relative humidity), irrespective of the coating level. In contrast, in the case of DBS and Myvacet, this type of relationship was only observed at low coating levels (5%). At intermediate coating levels (around 7.5%), the curing conditions had virtually no effect on drug release. At high coating levels (10%), the release rate initially increased and then decreased with increasing harshness of the curing conditions. This more complex behavior might be attributable to the superposition of two competing phenomena: improved film formation and drug migration into the polymeric membrane. Furthermore, it could be shown that the type of plasticizer had a major effect on drug release in not fully coalesced and equilibrated film coatings, whereas the release profiles were similar for all plasticizers in the case of completely formed and equilibrated film coatings. Importantly, the latter systems were stable for long term even during storage under stress conditions.

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.

Indices of tableting performance and application of percolation theory to powder compaction

Abstract The mechanical properties, tensile strength and identation hardness of compacts of different excipients with brittle or plastic characteristics are discussed, using two approaches on powder compaction. The first one, Leuenbergers exponential model extended later by percolation theory, is used to determine the compactibility, the compressibility and the characteristic relative density ( ϱ r ∗ ) of the compacts. Characteristic relative density ϱ r ∗ is the point when the first stable pharmaceutical compact is obtained. The second approach characterises the compact properties by using dimensionless indices, Hiestands indices, which give insight about relative tableting performance of materials. This study showed that the two approaches are complementary. In fact, when the relative density of excipients with plastic behaviour is increased, the bonding index increases. This evolution may be interpreted by the percolation theory for the region of dense compacts by the assumption of a difference in the percolation thresholds ϱ p ∗ , and ϱ σ ∗ obserbed from indentation hardness and tensile strength measurements respectively. The appearance of these transitions by ‘out-of-die’ measurements of the compaction properties of the studied excipients is similar to that observed earlier by the application of percolation theory to ‘in process’ compaction measurements.

The Effects of Relative Humidity and Super-Disintegrant Concentrations on the Mechanical Properties of Pharmaceutical Compacts

The influence of the composition and the relative humidity on the properties of pharmaceutical compacts prepared from mixtures of three excipients and three super-disintegrants was evaluated. Various amounts of super-disintegrant and different conditions of relative humidity during the storage were used to study mechanistically the disintegration process and to connect it to compacts mechanical properties. Three point single beam test was used to measure tensile strength and Youngs modulus of compacts containing various amount of disintegrant and stored under various relative humidity. The presence of moisture within pharmaceutical compacts containing a disintegrant influences drastically their mechanical properties. Then, the results are related to micro-cracks visualized by MEB.

Direct evidence for symmetry control in cyclodextrin-water interactions

Abstract The cyclodextrins, cyclic oligosaccharides possessing generally 6, 7, or 8 α, 1 –4 linked glucopyranose units, are widely used for the solubilisation and transport of organic molecules in aqueous media.3 Their solubilities 145 gL−1, α-Cd; 20 gL−1, β-CD; 220 gL−1, γ-CD, are considerably lower than those of simple saccharides and in particular that of β-CD, the most widely available compound, is anomalously low. We have previously shown that the solubilities arise from symmetry determined interactions of the CDs with the dynamic hexagonal structure of water. In the case of the unmodified cyclodextrins all three compounds exist in solution as large aggregates, thus the solubility of these systems is controlled by the interactions between these hydrogen bonded aggregates and the hydrogen bonding networks present in water. In the case of α- or γ-CD there are favorable overlaps with the hexagonal water structure, however for the seven-fold symmetry of β-CD no such favorable interactions can occur betwe...