G. Couarraze

Study of the mechanisms of formation of nanoparticles and nanocapsules of polyisobutyl-2-cyanoacrylate

Abstract Biodegradable colloids suitable for use as drug delivery systems can be formed by in situ polymerization of isobutylcyanoacrylate monomers. In this work we have studied the mechanisms of formation of colloidal systems of PIBCA obtained in the presence of oil and ethanol. For this different analytical techniques have been used (TEM, PCS, GPC). The results have shown that the diffusing ethanol was the most important factor which leads to the structure and colloidal characteristics of the particles by convective effects, the oil playing the role of a monomer support. The existence of an ideal oil/ethanol ratio (2:100) seems to result from the combination of both mechanisms. In the absence of oil and ethanol, IBCA polymerization occurs within micelles appearing in the aqueous phase. However, in the case of nanocapsule formation, owing to the solubility of the monomer in the organic phase and the diffusibility of ethanol, polymerization can develop at the interface. In this latter case, the formation of a double population of nanocapsules and nanoparticles probably arises from the breakdown of the same interfacial polymer.

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.

Hardness of moist agglomerates in relation to interparticle friction, granule liquid content and nature

Abstract Wet agglomerates deform plastically until they break through crack propagation. On the particulate level, liquid bridges are responsible for the strength of the wet agglomerate as they hold the particles together. The experiments reported in this paper identify the role of liquid surface tension, bridge Laplace pressure and liquid viscosity, which, in combination, explain the axial strength of pendular liquid bridges. Different situations exist depending on the degree the liquid wets the particles, and on the saturation of the agglomerate mass. A parabolic approximation can be used to describe the shapes adopted by pendular liquid bridges. On the wet agglomerate level, the hardness is related to three factors: the liquid binder surface tension and viscosity and the interparticle friction. A simple model is developed in this paper, based on the powder and liquid binder properties, which shows that the forces due to interparticle friction are generally predominant in wet agglomerates made from non-spherical particles. Although mechanical interlocking is not predicted, this model yields accurate prediction of wet agglomerate hardness independently measured on wet masses of varying composition. This theoretical hardness could prove an interesting tool for wet granulation research and technology.

Design of triptorelin loaded nanospheres for transdermal iontophoretic administration

Triptorelin is a decapeptide analog of luteinizing hormone releasing hormone, currently used for the treatment of sex-hormones dependents diseases. The aim of this work was to prepare triptorelin-loaded nanospheres useful for transdermal iontophoretic administration. Nanospheres were prepared with the double emulsion/solvent evaporation technique. The effect of three parameters on the encapsulation efficiency has been determined: the role of the pH of the internal and external aqueous phases, the nature of the organic solvent and the effect of three different poly(lactide-co-glycolide) (PLGA) co-polymers. Particle size, zeta potential and release kinetics were also determined. The encapsulation efficiency varied from 4 to 83% reaching the maximum value when both the internal and the external water phases were brought to pH 7 (isoelectric point of the peptide), methylene chloride was used as solvent of the copolymers and PLGA rich in free carboxylic groups was employed. The release profiles obtained with this co-polymer were characterized by the absence of burst effect. This behavior as well as the high encapsulation efficiency was explained by an ionic interaction occurring between the peptide and the co-polymer. This supports the already expressed theory that the release of peptides and proteins from PLGA nanospheres is also governed by the affinity of the encapsulated molecule versus the polymer. The obtained nanoparticles, regarding their size, amount encapsulated and zeta potential, were shown to be suitable for transdermal iontophoretic administration.

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.

Physical evaluation of a new patch made of a progestomimetic in a silicone matrix

The adhesion of a new Transdermal Therapeutic System (TTS) made of silicone and loaded with a progestomimetic drug was characterised. The goal of this study was to use well-known methods or to adapt them to collect representative data. Individually, methods such as surface tension, peel test and rheology are already widely used. Results show that the choice of a substrate for peel tests can be made in the light of surface tension data and that polymers like poly(tetrafluoroethylene) (PTFE) are good alternatives to skin. Peeling characterisations are made a function of thickness of films, drug content in active, conditions of preparation and conditions of use such as pressure. Dynamic rheology is more difficult to link to other methods as it mainly reflects internal phenomena and properties that arise in the bulk, as opposed on its surface. Master curves enable results to be used more easily, but the theories to interpret the data are still not powerful enough to replace peel testing.

Modelling of drug release from pellets coated with an insoluble polymeric membrane

Abstract In this work, a model is proposed to accurately describe drug release kinetics from coated pellets where the membrane does not entirely control the release. To validate the model, ketoprofen pellets prepared using the extrusion-spheronisation process, were coated with a membrane comprising acrylic resins (either 100% Eudragit RL or 50% Eudragit RL and 50% Eudragit RS) and different plasticizers. The effect of the membrane composition on drug release from coated pellets was investigated using the USP dissolution paddle method. In addition, permeation kinetics through free films made with the coating polymers were performed. The model permitted to quantitatively correlate the release kinetics from coated pellets with permeation properties of free films by taking into account the physical parameters of the systems. The advantage of this model is the possibility of ab initio optimization, from easy experiments not including coated pellets: drug release from uncoated matrices and permeation kinetics through free films.

Permeability of progesterone and a synthetic progestin through methacrylic films

Abstract The permeation for progesterone and a synthetic progestin was determined through films prepared from a hydrophilic acrylate-methacrylate copolymer (Eudragit R ). Steroid permeabilities allow us to evaluate a partition coefficient between films and water which is 5 times lower for the synthetic progestin: this difference is due to the higher aqueous solubility of this molecule despite the presence of a hydroxyl group which may interact with the polymer cation content. The values of partition coefficients show that both steroids are dissolved into the polymer films. From permeation experiments, diffusion coefficients are also calculated and different mechanisms of diffusion are presented which are ‘pore’ and ‘solution diffusion’. The values of the diffusion coefficients show that the main mechanism is solution diffusion according to the steroid solubilities in the polymer films.

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.

Powder dynamic contact angle measurements: Young contact angles and effectively wet perimeters

Abstract Dynamic contact angle (DCA) measurements on powder are of great interest for the prediction of various processes. Powder covered slides exhibit rough surfaces on which the definition of the Young contact angle is not straightforward. This paper proposes a semi-empirical model, which relates the Young contact angle to the measured immersion load of rough slides: ΔF0=γLV×[P+cosθY×po An effective wet perimeter, p0 is introduced as well as a mean contact line resistance, P × γLV. Both factors appear to describe well experimental measurements on test surfaces where various defects are created. As a result, DCA measurements can be adapted to any powder from very fine to very large, as proved on lactose powder and granules.