Sophie Cazalbou

Adaptative physico-chemistry of bio-related calcium phosphates

The mineral/organic ratio, the crystal dimensions, the stoichiometry and the surface properties of biological apatites in various mineralized tissues are controlled and adapted to reach specific properties. We proposed a model of a structured hydrated layer, located at the surface of apatite nanocrystals, which comprises ionic non-apatitic environments responsible for nanocrystalline apatite reactivity and evolution (maturation, ion mobility and adsorption properties). Understanding this adaptative ability is useful in the design of treatments for bone diseases and also in the preparation of bioactive biomaterials for bone filling, replacement and reconstruction.

Ibuprofen-loaded calcium phosphate granules: Combination of innovative characterization methods to relate mechanical strength to drug location

This paper studies the impact of the location of a drug substance on the physicochemical and mechanical properties of two types of calcium phosphate granules loaded with seven different contents of ibuprofen, ranging from 1.75% to 46%. These implantable agglomerates were produced by either low or high shear granulation. Unloaded Mi-Pro pellets presented higher sphericity and mechanical properties, but were slightly less porous than Kenwood granules (57.7% vs 61.2%). Nevertheless, the whole expected quantity of ibuprofen could be integrated into both types of granules. A combination of surface analysis, using near-infrared (NIR) spectroscopy coupling chemical imaging, and pellet porosity, by mercury intrusion measurements, allowed ibuprofen to be located. It was shown that, from 0% to 22% drug content, ibuprofen deposited simultaneously on the granule surface, as evidenced by the increase in surface NIR signal, and inside the pores, as highlighted by the decrease in pore volume. From 22%, porosity was almost filled, and additional drug substance coated the granule surfaces, leading to a large increase in the surface NIR signal. This coating was more regular for Mi-Pro pellets owing to their higher sphericity and greater surface deposition of drug substance. Unit crush tests using a microindenter revealed that ibuprofen loading enhanced the mechanical strength of granules, especially above 22% drug content, which was favorable to further application of the granules as a bone defect filler.

Comparison of low-shear and high-shear granulation processes: effect on implantable calcium phosphate granule properties

Background: Calcium phosphate porous ceramics present a great interest not only as complex bone defect fillers but also as drug delivery systems. Most of the methods described in the literature to fabricate pellets are based on compaction, casting into spherical molds, or on processes such as liquid immiscibility or foaming. Despite wet granulation is used in a wide range of applications in pharmaceuticals, food, detergents, fertilizers, and minerals, it is not applied in the biomaterial field to produce granules. Methods: In this study physicochemical and in vitro drug delivery properties of implantable calcium phosphate granules, produced by two wet agglomeration processes, were compared. Pellets obtained by high shear granulation (granulation in a Mi-Pro apparatus) were shown to be more spherical and less friable than granules elaborated by low shear process (granulation in a Kenwood apparatus). Although Mi-Pro pellets had a slightly lower porosity compared to Kenwood granules, ibuprofen loading efficiency and dissolution profiles were not statistically different and the release mechanism was mainly controlled by diffusion, in both cases. Conclusion: Mi-Pro pellets appeared to be better candidates as bone defect fillers and local drug delivery systems as far as they were more spherical and less friable than Kenwood agglomerates.

The pressure–volume–temperature relationship of cellulose

Pressure–volume–temperature (PVT) measurements of α-cellulose with different water contents, were performed at temperatures from 25 to 180xa0°C and pressures from 19.6 to 196xa0MPa. PVT measurements allowed observation of the combined effects of pressure and temperature on the specific volume during cellulose thermo-compression. All isobars showed a decrease in cellulose specific volume with temperature. This densification is associated with a transition process of the cellulose, occurring at a temperature defined by the inflection point Tt of the isobar curve. Tt decreases from 110 to 40xa0°C with pressure and is lower as moisture content increases. For isobars obtained at high pressures and high moisture contents, after attaining a minimum, an increase in volume is observed with temperature that may be related to free water evaporation. PVT α-cellulose experimental data was compared with predicted values from a regression analysis of the Tait equations of state, usually applied to synthetic polymers. Good correlations were observed at low temperatures and low pressures. The densification observed from the PVT experimental data, at a temperature that decreases with pressure, could result from a sintering phenomenon, but more research is needed to actually understand the cohesion mechanism under these conditions.

Validation of a manufacturing process of pellets for bone filling and drug delivery

Wet high shear granulation followed by heat treatment was used to manufacture calcium phosphate porous spherical pellets. Experimental conditions were determined in order to obtain pellets presenting required specifications, i.e. size of about 800 μm, maximum sphericity and high microporosity. These pellets were intended for bone defect filling and in situ drug delivery and the final step therefore consisted in ibuprofen loading. In a context of quality assurance, the aim of the present work was to validate each step of the manufacturing process (i.e. granulation, calcination and drug loading). Indeed, reproducibility of the pellet characteristics, especially the drug content and release kinetics from the ceramic to be implanted, has to be ensured through the manufacture quality control.