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Scaling-up the extrusion-spheronization process involves the separate scale-up of each of the five process steps: dry mixing, granulation, extrusion, spheronization, and drying. The aim of the study was to compare two screw extrusion systems regarding their suitability for scaling-up. Two drug substances of high- and low-solubility in water were retained at different concentrations as formulation variables. Different spheronization times were tested. The productivity of the process was followed up using the extrusion rate and yield. Pellets were characterized by their size and shape, and by their structural and mechanical properties. A response surface design of experiments was built to evaluate the influence of the different variables and their interactions on each response, and to select the type of extrusion which provides the best results in terms of product quality, the one which shows less influence on the product after scale-up ("scalability") and when the formula used changes ("robustness"), and the one which allows the possibility to adjust pellet properties with spheronization variables ("flexibility"). Axial system showed the best characteristics in terms of product quality at lab and industrial scales, the best robustness at industrial scale, and the best scalability, by comparison with radial system. Axial system thus appeared as the easiest scaled-up system. Compared to lab scale, the conclusions observed at industrial scale were the same in terms of product quality, but different for robustness and flexibility, which confirmed the importance to test the systems at industrial scale before acquiring the equipment.

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 compact's mechanical properties. Three point single beam test was used to measure tensile strength and Young's 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.

Percolation theory has been applied to several mechanical properties of pharmaceutical tablets. This power law describes the change of tablet's properties with the relative density. It defines critical tablet densities from which the mechanical properties start to change. The exponent in the law is expected to be universal for a mechanical property and numerical values are proposed in the literature. In this work, the percolation model was applied to the tensile strength and the reduced modulus of elasticity (obtained from surface indentation test) of three compacted pharmaceutical excipients (a microcrystalline cellulose, a lactose and an anhydrous calcium phosphate). Two approaches were proposed. First, the exponent was kept constant and equal to the values used in the literature (2.7 for the tensile strength and 3.9 for the reduced modulus of elasticity). Secondly, the critical tablet density (i.e. the percolation threshold) and the exponent were determined from the model. In the first approach, the percolation thresholds were higher than the relative tapped density. Using the second approach, the experimentally determined exponents were not close to the values of the literature and the critical relative densities were higher than the relative tapped density or equal to zero. Then, this study showed that the exponent seems not universal and that the model must be used carefully.

The major aim of this study was to get deeper insight into the process of polymer cross-linking and the resulting structure of beads based on chitosan (CS) or chitosan/poly(ethylene oxide) (CS/PEO) semi-interpenetrating networks (semi-IPNs) as new carrier materials for oral drug delivery. Spherical hydrogels were prepared by a dropping method. The uptake kinetics of the cross-linking agent glyoxal into the beads were monitored and quantitatively described using Fick's second law of diffusion. High-resolution synchrotron infrared microspectroscopy (SIRM) was used to characterize the inner structures of the beads. Importantly, the diffusion of glyoxal through the hydrogels was found to be much slower than the cross-linking reaction and the mesh size of the created networks to be much larger than the hydrodynamic diameter of glyoxal. The presence of PEO chains slightly decreased the diffusivity of glyoxal due to obstruction effects. However, the cross-linking reaction was not affected. Interestingly, the polymers were homogeneously cross-linked throughout the beads, except for a thin outer shell showing an elevated cross-linking density. Thus, the obtained cross-linked hydrogel-based beads exhibit well-defined polymeric structures and offer an interesting potential as novel oral drug delivery systems.

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.

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.

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.

Formulation scientists generate physicochemical data that are used in process modelling and in the prediction of end-product quality. In this respect, contact angles are of particular importance as the surface energy of substances influences their processability and bioavailability. Dynamic contact angle (DCA) analysis represents a straightforward wettability assay. Now fully adapted to powders, DCA analysis also proves to be more efficient than other methods for wettability determination.

Purpose: The main goal of this study was to develop an ocular controlled release formulation of a model oligonucleotide (pdT16), contained within liposomes dispersed within a thermosensitive gel composed by poloxamer 407., Methods: The influence of the poloxamer concentration 2% or 27% on the stability of the liposomes (PC: CHOL and PC: CHOL: PEG-DSPE) was investigated. The in vitro release profiles of pdT16 from various poloxamer formulations (free pdT16 dispersed within 20% and 27% poloxamer gels, pdT16 encapsulated within liposomes dispersed within 20% and 27% poloxamer gels) were realized using a membrane-free release model., Results: The dispersion of liposomes within a dilute 2% poloxamer solution resulted in a great leakage of pdT16 from liposomes. However, the destabilization effect of poloxamer was reduced when higher concentration (27%) was used. Poloxamer dissolution was found to control the release process of pdT16, whereas the dispersion of liposomes within 27% poloxamer gel was shown to slow down the diffusion of pdT16 out from the gel., Conclusions: The dispersion of liposomes within a 27% poloxamer gel presented an interesting system to control the release of a model oligonucleotide compare to a simple gel.

Unlabelled: Experiments were performed on rabbits randomly assigned to intracisternally receive 0.3 mL of plain bupivacaine 5 mg/mL, liposomal bupivacaine 5 mg/mL, bupivacaine-free liposomes, or isotonic phosphate-buffered saline. Mechanical ventilation was initiated or intravenous dopamine was infused when respiratory depression or hypotension occurred. Seven days after the injection, the whole spinal cord was removed and histopathologic characteristics were studied on transverse sections. All preparations were devoid of phosphatidylcholine hydrolysis or oxidation compounds. Solutions without bupivacaine produced transient irritative signs that required sedation in most rabbits. Despite the similar duration of respiratory depression in groups receiving liposomal or plain bupivacaine, liposomes produced significantly prolonged motor blockade (126 vs 70 min). Correction of hypotension after plain bupivacaine required a longer dopamine infusion and larger doses than after liposomal bupivacaine (28 vs 18 min and 74 vs 47 mg). Necrosis was observed in the cervical area of two rabbits (one in the liposomal bupivacaine group and another in the phosphate buffer group). No demyelinated areas were noted in spinal cord examinations. We conclude that liposomal bupivacaine leads to a less severe sympathetic block and to a prolonged motor block, whereas histologic changes are not significantly different among groups., Implications: Multilamellar liposomes containing bupivacaine administered intracisternally to rabbits produce spinal cord histopathologic changes not significantly different from those observed with plain bupivacaine. Sustained release of bupivacaine from liposomes is suggested by the prolonged motor blockade and the reduced severity of arterial hypotension. Use of these liposomes could prolong the local anesthetic effects of bupivacaine.

Purpose: The feasibility of using iontophoresis to enhance the permeation rate of a model peptide was investigated in vitro using hairless mouse skin., Methods: Angiotensin 2 (AT 2) was employed as a permeant probe, using optimum iontophoresis conditions. A number of physicochemical parameters (donor ionic strength; valence of competitive ions; pH of donor solution) were studied with the aim of exploring the mechanisms involved in the iontophoretic transport through the skin: electrokinetic transport or convective transport. For this purpose, the magnitude of the convective solvent flow was also evaluated by the permeation of (3H) H2O. The interest of pulsed currents for peptide delivery was also investigated and the effect of current density and frequency was studied., Results: AT 2 transport was found to be enhanced 20-fold in comparison to passive permeation and was found to be proportional to the current density with direct currents as with pulsed currents., Conclusions: Although the flux enhancement of ions during iontophoresis is due principally to the electrical potential gradient, secondary effects such as convective solvent flow contribute also to flux enhancement of peptide delivery. This effect is dependent of physicochemical conditions of formulation.

The study of diffusion in a polymeric system often poses difficult experimental problems, notably when the rate of release is determined in a liquid receptor phase which can interact with the system. In this publication, we propose two experimental methods to determine the diffusion coefficient by a gel-gel kinetic release study, in which the receptor is a same gel unloaded initially. The first method is based on the use of radioactive tracers and a multi-channel radioactivity counter to obtain, at different times, the concentration profiles in the diffusion medium. The theoretical model is given for a gel donor with the concentration C0 of diffusing molecules is below or above the solubility Cs. The second method is based on the measurement of the displacement of solubility front during the diffusion within the system in the case C0 > Cs. The theoretical model shows that this displacement is a function of square root of t. For illustration, two experimental determinations of testosterone diffusion coefficient on the one hand in a silisic acid gels and on the other hand in an acrylic acid gels are given.