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.

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, Espcp and specific expansion energy, Espexp). It was observed that for the mixtures studied, the change of Espcp with the mass composition could be fitted using a linear relationship (it was not the case with Espexp). 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.

Physico-chemical properties of a substance including the compaction behaviour are directly connected with the crystalline structure. The aim of this work is to compare the compaction behaviour in a group of excipient and in this first part, to display the influence of lactose structures on the compressibility.alpha-Lactose monohydrate (LalphaM), anhydrous beta-lactose (LbetaA), anhydrous alpha-lactose (LalphaA) and partly amorphous lactose (FF) were compressed using instrumented presses to investigate the densification behaviour under pressure. Force-displacement curves were associated to two energy parameters, specific cycle energy and specific expansion energy. This approach was used to class the four lactose species. It is possible to differentiate three groups with the specific energy cycle, FF, LalphaA/LbetaA and LalphaM in decreasing order of this energy. At the same time, the values of specific expansion energy are relatively low for FF and LalphaA contrary to LalphaM and LbetaA.Then, Heckel's plots were obtained with two compact geometries and the mean yield pressure was calculated from the in-die-method and the out-of-die-method. Two lactoses seem to differ, LalphaM appears to be the most ductile whereas LalphaA is more brittle than the others.Finally, it is concluded, that in the case of lactoses, pseudopolymorphism seems to affect the compressibility more than anomerisation or partial amorphisation. (C) 2004 Elsevier B.V. All rights reserved.

An analysis of the power consumption during encapsulation shows the benefits of characterizing and quantifying the wet-powder mass consistency during kneading complexation.

It is well known that the choice of the crystal form affects the physicochemical properties such as compaction behaviour. In this work, the mechanical properties of compacts obtained from compaction of lactoses by using a micropress prototype are calculated. Tensile strength, Young's modulus, toughness and Brinell hardness were measured and used to compare the various crystalline forms: α-lactose monohydrate (LαM), anhydrous β-lactose (LβA), anhydrous α-lactose (LαA) and partly amorphous lactose (FF). With all the mechanical properties measured, the lactoses could be differentiated. Then, the specific energy of failure GIC∗ was obtained from the toughness and the Young's modulus for each lactose. LαM showed small specific energy of failure due to its low toughness which is not balanced by its Young's modulus. The highest values were obtained with the two anhydrous forms, LαA and LβA. Finally, these mechanical properties were linked with general compaction behaviour and cohesive energy density which is a characterization at a molecular level.

Beads of chitosan (CS) crosslinked network and of chitosan/poly(ethylene oxide) (CS/PEO) semi-interpenetrating network (semi-IPN) were prepared by a dropping technique and characterized. PEO content in the beads of semi-IPN was determined by gel permeation chromatography. CS crosslinking ratio was evaluated qualitatively by ATR-FTIR spectroscopy and quantitatively by UV spectrophotometry. After drying in a fluidized bed apparatus, a monodisperse population of well individualized, spherical, and smooth particles was obtained. It was shown that bead collapsus during the drying stage was avoided thanks to the chemical crosslinking of CS chains. By the prilling, or laminar jet break-up technology, production at a larger scale was also achieved. This process allowed the formation of a row of well calibrated drops of polymer solution under the influence of a vibration. Polymer solution characteristics, particularly viscosity, constituted a critical factor in the feasibility of the prilling process. Transposition of the formulation was managed through the optimization of process parameters such as vibration frequency, amplitude, and flow rate. (C) 2004 Wiley Periodicals, Inc.

The aim of this study was to enhance the low solubility of eflucimibe, a new chemical entity which can be used as medicine to treat dyslipidemiae, by complexation with γ-cyclodextrin. The complex was prepared using kneading method. The interaction evolution was studied during process by comparison of the semi-solid and physico-chemical states of the product. The evolution of the semi-solid state was followed by torque measurement when the evolution of physico-chemical state was studied by differential scanning calorimetry, infrared spectroscopy and by determination of the drug solubilisation profile. The interaction, which occurs during the process, is characterised by a modification of the product consistency and by a disappearance of the drug endothermic peaks, a disappearance of a drug spectral band and a widely improvement of the drug solubilisation profile. Indeed, after complete interaction, the drug quantity solubilised in specific conditions increased about 44-fold compared to those of untreated drug. Moreover, the comparison of the physico-chemical and semi-solid states during kneading process clearly shows that when the interaction takes place, a solidification of the paste occurs. The results of these works suggested that the formation of new solid phase allows an enhancement of the solubility of eflucimibe.

Multilamellar vesicles called Spherulites have recently been discovered and are being developed for encapsulation applications. In this study, we present new systems of Spherulites called complex dispersions. These are prepared by dispersing Spherulites within an oily medium, and then emulsifying this oily dispersion of Spherulites within an aqueous solvent. The ability of complex dispersions to reduce the release of encapsulated ions under variable osmotic dilutions was evaluated and compared with Spherulites directly dispersible in an aqueous medium, and with multiple emulsions. An advantage of complex dispersions over Spherulites is to present an additional oily barrier. Indeed, this barrier retarded the release of encapsulated ions. Complex dispersions also proved to be less sensitive to osmotic pressure than multiple emulsions. It appeared that the dilution of a complex dispersion formulated with no external aqueous phase containing a hydrophilic surfactant provided the slowest release of encapsulated ions. Furthermore, this formulation maintained a difference of pH between the internal and external aqueous phases for a few hours. In conclusion, these new systems of Spherulites known as complex dispersions show great potential for pharmaceutical applications such as controlled release and protection of encapsulated substances.

Spherulites® are multilamellar vesicles made up of surfactant bilayers. These vesicles would potentially be very useful for the encapsulation and protection of molecules; however, traditional formulations of these vesicles are poor at retaining small hydrophilic molecules (below 1000 g/mol). In this study, we present new systems of Spherulites called complex dispersions. These are prepared by dispersing Spherulites in an oil medium, and then emulsifying this oily dispersion of Spherulites within an aqueous solvent. These new systems provide an additional oil barrier between encapsulated molecules and an external aqueous phase. We have used polarized light optical microscopy, X-ray diffraction and freeze–fracture electron microscopy to study a complex dispersion of Spherulites at all stages of its preparation. We first studied the sheared lamellar phase, followed by the dispersion of the multilamellar vesicles in the oily medium and finally the emulsification of the oily dispersion within the aqueous solvent. We compared our results on lamellar phases with previous results obtained with Spherulites directly dispersible in an aqueous medium. Since the formulation of our lamellar phase included a large percentage of oil as a component, we studied the localization of the oil in the lamellar structure. We also studied the influence of osmotic pressure on complex dispersions, because complex dispersions possess a double structure similar to that of water-in-oil-in-water emulsions and multiple emulsions are known to be sensitive to osmotic pressure. In conclusion, complex dispersions proved to be new potential carriers exhibiting some unique physical properties.

Two kinds of chitosan-based hydrogels, a crosslinked chitosan reference gel and a chitosan-poly(ethylene oxide) semi-interpenetrating network (semi-IPN), with potential pH-sensitive swelling and drug delivery properties are characterized. Swelling studies were performed on the two kinds of hydrogels by differential scanning calorimetry (DSC) at pH 1.2 and by the gravimetric method at pH 1.2 and pH 7.2. Both methods lead to similar results. If pH-dependent swelling properties were observed with both hydrogels, they were however improved for the semi-IPN. The amount of bound water in the xerogels could be determined from DSC measurements and a thermogravimetric analysis. The results obtained by both techniques were in good agreement and indicated that the semi-IPN contained more bound water than the reference gel probably due to the presence of the hydrophilic poly(ethylene oxide) chains. Young modulus of the swollen hydrogels was determined by indentation analysis. The semi-IPN displayed improved mechanical properties compared to the reference gel.

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.

In this paper we describe how the spherical crystallization process by QESD method can be applied to a water-soluble drug, salbutamol sulfate. The type of solvent, antisolvent, and emulsifier and the concentration of emulsifier to be used for the production of spherical particles with a size range 80-500 microm are determined. Furthermore, the solvent/antisolvent ratio and the temperature difference between them (Delta T) are studied. It was observed that, in the case of salbutamol sulfate, the Delta T value has no influence on the formation of spherical particles. A very large metastable zone of salbutamol sulfate in water could explain this phenomenon. Finally, the influence of emulsifier concentration and of maturation time on the size of spherical particles is studied. The results show that these two parameters must be fixed to control the size of the recovered particles.

Poorly-compressible crystals of ketoprofen were agglomerated by spherical crystallization with a two-solvent system (acetone/demineralized water). By varying the operating parameters (temperatures and concentrations), we have modified the shape and the internal texture of the particles obtained. On the other hand, preliminary screening of polymers highlighted three formulations with very low concentrations of additives. The micromeritic features of all these systems were studied to evaluate the improvement of compressibility and compactibility for direct tabletting.

Wet granulation processes frequently rely on the device power consumption profile to monitor the process endpoint. This work shows how the observed power consumption relates to the physical properties of the mass. The liquid binder was traced with a fluorescent marker and the liquid distribution could be followed during the process. It was found that primary agglomerates form in the reactor, the shape and composition of which depend on the wettability of the starting powders by the liquid binder. An increase of the device power consumption is conditional to the disruption of these primary agglomerates. Increasing the viscosity of liquid binders up to 250 mPa. s had no significant effect on the power consumption. Eventually, the lower surface tension liquid binders yielded greater energy consumption, indicating that interparticle friction forces had a great impact on the device power consumption.

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. (C) 2001 Elsevier Science B.V. All rights reserved.

Granulation is an important process in the pharmaceutical industry for the preparation of solid dosage forms. For high-shear wet granulation, the process endpoint is monitored using the device power consumption. However, granulation is very sensitive to variations in the feed product physicochemical properties and, in some cases, power consumption profiles can not be used for process control. In this paper, a model is proposed to predict the granulation overwetting point from the spreading energy of the liquid binder on the powder. This energy is independently calculated from measurements of the powder true surface area, liquid binder surface tension, and liquid contact angle on the powder surface.

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=dref/di) 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.

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.