Marylène Viana

About pycnometric density measurements

Pycnometric density is at the moment the closest approximation of true density calculated from the molecular weight and crystalline lattice of the product. It is determined by using helium pycnometers that offer the advantage of being easy-to-use and rapid, especially fully automated apparatus. If the accuracy and the reproducibility of the technique are sufficient to reveal minute variations, this data is of interest for characterisation of crystalline structures (polymorphs, pseudopolymorphs, amorphous state), detection of defects, pores or impurities, and possible changes in crystal density during compaction. The aim of this article is to investigate on the confidence that can be expected when measuring density with an AccuPyc 1330 pycnometer. The experiments carried out on glass beads, quartz and mannitol have shown that operating parameters can affect the accuracy of pycnometric density to the nearest 0.01 g cm(-3). If measurements are performed in optimal conditions, 0.02% accuracy can be obtained, otherwise it can fail to 0.1% or less, depending on the material and the variations in the standard volume.

Use of cycles of compression to characterize the behaviour of apatitic phosphate powders

A method has been developed to analyse the bulk and mechanical properties of powders under pressure using a uniaxial press. This easy-to-use and rapid method requires small amounts of material and allows different compression parameters to be assessed. Classical parameters, e.g. compaction ratio and tensile strength, are determined. The recording of the compression and rupture cycles allows the energies of compression and of rupture to be calculated. The flowability of the powder is determined during the compression experiment. The energy of compression is linked with the elastic energy to help to explain the energy consumption during compression. It is also correlated to the rupture energy to evaluate the ability of the material to convert the energy of compaction into cohesion. This simple method has been applied to apatitic calcium phosphate powders differing in Ca/P molar ratio and/or crystallinity. It allowed to study the relation between chemical nature and compressibility.

Multiphase versus Single Pot Granulation Process: Influence of Process and Granulation Parameters on Granules Properties

ABSTRACT High-shear wet granulation is widely used for the production of pharmaceutical dosage forms. Different equipment is available for high-shear granulation and drying. This review focuses on two main processes for granules production: multiphase consisting of high-shear granulation followed by drying in a separate apparatus, and single pot granulation/drying. At present, formulas are specifically developed with regard to the production equipment, which raises many problems when different industrial manufacturing equipment is used. Indeed, final granules properties are likely to depend on equipment design, process, and formulation parameters. Therefore, a good understanding of these parameters is essential to facilitate equipment changes. The aim of this review is to present the influence of equipment, process, and formulation parameters on granules properties, considering both the granulation and the drying steps of multiphase and single pot processes.

Comparison of Three Dissolution Apparatuses for Testing Calcium Phosphate Pellets used as Ibuprofen Delivery Systems

Porous calcium phosphate pellets were produced according to two granulation processes (low and high shear wet granulations) and drug loaded with five ibuprofen contents (1.75%, 7%, 12.5%, 22%, and 36%) in order to ensure both bone defect filling and local drug delivery. The drug-release kinetics from the two types of pellets was studied using three dissolution apparatuses: paddle apparatus, reciprocating cylinder, and flow-through cell. The paper compared the three dissolution methods and considered the effect of the granulation process on the ibuprofen-release kinetics. Dissolution data were analyzed using the Weibull function as well as the difference (f1) and similarity (f2) factors. Dissolution kinetics was not influenced by the granulation process, regardless of the dissolution apparatus and of the drug content. The comparison of the three dissolution devices indicated that ibuprofen was released faster from granules loaded with 36% of drug content with the reciprocating apparatus, due to the disintegration of the granules occurring during the dissolution test. For the other drug contents, dissolution profiles were not significantly different from one apparatus to another. However, the flow-through cell seemed to be more suitable for the drug-release study of implantable materials.

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.

Powder functionality test: a methodology for rheological and mechanical characterization.

In most pharmaceutical formulations, the part of the excipients, in quantity and number, is larger than that of active principles, justifying particular attention to their characteristics to ensure quality, efficacy, and reproducibility of final forms. Whereas chemical specifications are described in Pharmacopeias, physical characteristics, up to now, have not been sufficiently considered. Nevertheless, there is a need for tests to objectively compare technological performances of products and justify composition of medicinal products. The powder functionality test described in this article is based on the analysis of the global behavior of materials under pressure. The powder compression is performed using an instrumented uniaxial press, Lloyd 6000R, and a compression cell of 1 cm3 in volume, allowing a complete and early characterization with a few grams of material. Indices characterizing packing, densification energies, energetic yields, and deformation mode of the particles are proposed from the analysis of compression cycles. Cohesion and energy of rupture are deduced from the diametral rupture cycles of the compacts. Application of this methodology to supplied celluloses has shown better flow properties of microcrystalline celluloses due to their higher bulk density and particle size. The energy fraction lost as frictions is very important and independent of the type of celluloses, whereas elastic energy is higher for powdered celluloses P100 and G250. Finally the efficacy to convert compaction energy into cohesion is higher for products with a small degree of polymerization, i.e., microcrystalline celluloses, except A301 and A302, which also are distinguished by their low porosity.

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.

Dissolution of a surfactant-containing active porous material

We have studied the imbibition and dissolution of a porous material in two separate scenarios: (1) when the porous material contains a surfactant powder and (2) when the porous material is dissolved in a surfactant solution. We show that the dissolution kinetics in both scenarios is significantly affected by the presence of the surfactant and results in an increase in the characteristic imbibition time of the porous material, which can be well understood in the framework of the classical law of capillarity. Slowing of the imbibition kinetics was found to be affected by a modification of the liquid wetting properties, but is also affected by a variation in the solubility of the porous material in the presence of the surfactant. Furthermore, there is a depletion effect of the surfactant inside the rising liquid, which is in good agreement with previous work and theoretical predictions.

A novel application of the T-cell for flow-through dissolution: the case of bioceramics used as ibuprofen carrier.

This paper describes the use of a novel flow cell, the T-cell, adapted to the flow-through cell apparatus, for the study of ibuprofen release from implantable loaded pellets and its performance in comparison to the compendial tablet cell. In fact, the drug targeting with a local delivery system becomes increasingly used to achieve therapeutic doses directly on the implantation site while maintaining a low systemic drug level. Due to the long and expensive in vivo studies necessary to evaluate the efficacy of such delivery systems, in vitro dissolution techniques are performed despite there being no standard method in the biomaterial field. In this work, dissolution profiles obtained with the T-cell configuration clearly indicate a prolonged release of ibuprofen. Dissolution data fitted to Higuchi, Hixson-Crowell, Ritger-Peppas and Kopcha equations indicate the coexistence of diffusion and erosion mechanisms governing ibuprofen release. T-cell adapted to the standard flow-through dissolution apparatus is shown to better simulate in vivo conditions than the tablet cell. This is relevant for in vivo/in vitro correlations.

Interest of High Shear Wet Granulation to Produce Drug Loaded Porous Calcium Phosphate Pellets for Bone Filling

Spherical porous calcium phosphate pellets were fabricated by high shear wet granulation using native starch as a binder. After a heat treatment to eliminate the organic template, pellets were loaded with ibuprofen by solvent evaporation method. In vitro drug release kinetics was determined using an USP II apparatus (Prolabo Dissolution Tester, France). Results showed the interest of the calcination and of the increase in the binder-porogen content, to improve the drug loading (higher drug content) and prolong the release of the drug substance.