β-TCP porous pellets as an orthopaedic drug delivery system: ibuprofen/carrier physicochemical interactions.

Calcium phosphate bone substitute materials can be loaded with active substances for , targeted drug administration. In this study, porous β-TCP pellets were investigated as an anti-inflammatory drug carrier. Porous β-TCP pellets were impregnated with an ethanolic solution of ibuprofen.

Surface responses and desirability functions to determine optimal granulation domains.

Background: Single pot mixer-granulator-dryer (high-shear granulator with in situ double jacket vacuum drying) and multiphase equipment (high-shear granulator associated with fluid bed dryer) are classically used for wet granulation. At present time, industrial production imperatives may require to switch one formulation from one equipment to another.

Method: To compare the two processes and to define, for each of them, the optimal formulation domain, experiments were organized according to Doehlert experimental designs.

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.

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.

Comparison of single pot and multiphase granulation. Part 2: Effect of the drying process on granules manufactured in a single pot granulator and dried either in situ or in a fluid bed dryer.

The aim of this study was to highlight the effect of the drying process on granules manufactured in a pilot scale single pot granulator and dried either in situ or in a fluid bed dryer, for formulations differing in drug substance and its concentration (1%; 25%). Although most of raw data were within specifications, single pot drying tended to improve granule comprimability and seemed less sensitive to formulation. Moreover, it was demonstrated that the formulation impacted on granule median diameter, packing ability, comprimability, residual lower punch pressure and tablet dissolution kinetics.

Comparison of single pot and multiphase granulation. Part 1: Effect of the high shear granulator on granule properties according to the drug substance and its concentration.

Pharmaceutical granulations are usually developed with regard to a specific manufacturing process but switching from one piece of equipment to another can be necessary to comply with the available industrial equipment. Investigations were undertaken on formulations differing in the drug substance and in its concentration. Our aim was to highlight the effect of the granulation process on granules manufactured in a pilot scale Moritz Turbosphere TS50 or in Fielder PMA 65 and dried in a Glatt GPCG1 fluid bed dryer.

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.

Comparison of single pot and multiphase high shear wet granulation processes related to excipient composition.

At present time, industrial production imperatives can require the transposition of a formulation from one equipment to another. In order to evaluate the impact of such a switch on the properties of granules and tablets, investigations were undertaken on formulations manufactured both in a single pot mixer-granulator-dryer (high shear granulator with in situ double jacket vacuum drying) and in a multiphase equipment (high shear granulator/fluid bed dryer). Principal component analysis highlighted the major contribution of the binder ratio on granule size distribution, flow and packing ability whereas the relative ratio of mannitol and lactose, used as fillers, mainly impacted on compressibility and tablet cohesion.

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.

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.

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.

Fabrication of porous substrates: a review of processes using pore forming agents in the biomaterial field.

This paper is a review of solid and casting manufacturing processes able to create porous materials, mainly in the biomaterial field. The considered methods are based on pore forming agents that are removed either by heating or by dissolution. All techniques lead to products presenting pores with amount, size, and shape are close to those of the initial pore formers.

Influence of process parameters on pellets elaborated in a Mi-pro high-shear granulator.

The aim of the study was to prepare porous pellets several hundred micrometers in diameter into or onto which drug substances could be embedded. Wet granulation was carried out on a powder mix of alpha-lactose and polyvinylpyrrolidone in a Mi-Pro high-shear granulator. The process parameters were investigated to point out their influence on pellet physical properties.

Multiphase versus single pot granulation process: influence of process and granulation parameters on granules properties.

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.

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.

Talc functionality as lubricant: texture, mean diameter, and specific surface area influence.

Talc is widely used as a glidant (flow regulator) for powders. This study highlights the characteristics that confer to talcs new end use properties in improving the lubrication function during compression. We studied the contribution of texture, mean diameter (D50), and specific surface area on the residual die pressure, the ejection pressure, the lubrication index, and the tablet hardness.

Influence of manufacturing process on tabletting ability of powder: comparison between blending, grinding, and spray drying of two formulations made of theophylline and lactose/cellulose or Cellactose.

Three manufacturing processes were applied to two formulations composed of 20% anhydrous theophylline associated with either 20% microcrystalline cellulose and 60% lactose or 80% Cellactose. The processing method (dry blending, grinding, or spray drying) and the formulation were investigated through the comparison of the physical and flow characteristics and the compactibility of the end products. The results demonstrated that the formulation had a major effect on the mechanical properties, with binary blends exhibiting a higher resistance than ternary ones, whereas flow properties and densification depended on the process.

About the use of stoichiometric hydroxyapatite in compression - incidence of manufacturing process on compressibility.

Literature concerning calcium phosphates in pharmacy exhibits the chemical diversity of the compounds available. Some excipient manufacturers offer hydroxyapatite as a direct compression excipient, but the chemical analysis of this compound usually shows a variability of the composition: the so-called materials can be hydroxyapatite or other calcium phosphates, uncalcined (i.e.

Effects of true density, compacted mass, compression speed, and punch deformation on the mean yield pressure.

Compressibility properties of pharmaceutical materials are widely characterized by measuring the volume reduction of a powder column under pressure. Experimental data are commonly analyzed using the Heckel model from which powder deformation mechanisms are determined using mean yield pressure (Py). Several studies from the literature have shown the effects of operating conditions on the determination of Py and have pointed out the limitations of this model.

The use of energy indices in estimating powder compaction functionality of mixtures in pharmaceutical tableting.

A series of binary powder blends comprising of microcrystalline cellulose (Avicel PH101), alpha-lactose monohydrate or theophylline anhydrous were prepared in order to investigate the densification of binary pharmaceutical powder mixes under compaction pressure. It is postulated that the use of derived energy parameters, as well as various evolved indices, calculated from the work expended during the fabrication and/or rupture of a compact can be employed to quantitatively predict the compaction properties of pharmaceutical powder mixes comprised of the same constituents. The relationship between the net work of compression normalized to powder volume and the resulting compact strength for mix constituents can be used to define a pharmaceutical formulation space in which compact mechanical properties can be estimated for other 'virtual mixes' of the same constituents in different proportions.

The use of particle characteristics to elucidate mix homogeneity in binary powder blends.

A series of binary powder blends comprising microcrystalline cellulose (Avicel PH101), alpha-lactose monohydrate, or anhydrous theophylline were prepared in order to investigate the ability of particle-characteristics measurements to express the homogeneity of the resulting mixture. It is postulated that fundamental physical characteristics, such as particle-specific surface area, true density, and size distribution, can be used to quantitatively ascertain mix homogeneity in routine pharmaceutical blending operations.

[The therapeutic utilization of magnesium: medical consequences].

To optimize a pharmaceutical formulation, one has to take into account physicochemical, biopharmaceutical, therapeutical and technological properties of the active principle. These properties are investigated in the PREFORMULATION phase. The authors envisage dosage form (capsule) of magnesium and describe two aspects of the active principle: therapeutic and biopharmaceutic.

[The bioavailability of paracetamol II. The effect of porosity and mechanical properties of the dosage form on solubility].

The authors attempt to explain differences observed in dissolution rate of twelve different brands of paracetamol (nine tablets and three capsules) in terms of pore structure and tensile strength; the pore structure of both tablets and capsules is investigated by mercury porosimetry. Brands (tablets) which liberate paracetamol rapidly are characterized by a higher porosity value. Higher mean pore diameter signifies less t50 and higher porosity.

[The biodisposition of paracetamol. I. The kinetics of disintegration of some dosage forms].

The in vitro properties of twelve brands of paracetamol (nine tablets and three capsules), commercialized in France, are studied. Among the brands tested (tablets), Latepyrine and Gynospasmine are characterized by faster and Panasorb by slower dissolution rate. Total time of dissolution varies between 7 and 60 min.