Gilles Baylac

Release behaviour of clozapine matrix pellets based on percolation theory

The release behaviour of clozapine matrix pellets was studied in order to investigate if it is possible to explain it applying the concepts of percolation theory, previously used in the understanding of the release process of inert and hydrophilic matrix tablets. Thirteen batches of pellets with different proportions of clozapine/microcrystalline cellulose (MCC)/hydroxypropylmethyl cellulose (HPMC) and different clozapine particle size fractions were prepared by extrusion-spheronisation and the release profiles were studied. It has been observed that the distance to the excipient (HPMC) percolation threshold is important to control the release rate. Furthermore, the drug percolation threshold has a big influence in these systems. Batches very close to the drug percolation threshold, show a clear effect of the drug particle size in the release rate. However, this effect is much less evident when there is a bigger distance to the drug percolation threshold, so the release behaviour of clozapine matrix pellets is possible to be explained based on the percolation theory.

The Improvement of Ibuprofen Dissolution Rate Through Microparticles Spray Drying Processed in an Aqueous System

A study to enhance the dissolution rate of ibuprofen, a poorly water-soluble drug, was carried out through combining specific formulations and processes with the addition of a hydrophilic carrier for the preparation of microparticles. Microparticle production was performed by spray drying ibuprofen microsuspensions formulated in an aqueous system with the addition of ethanol containing Aerosil 200® and Tween 80®. We were able to consistently produce microparticles as much as 40% of the dry weight of the input microsuspension. Spray-dried microparticles were characterized by scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, laser diffractometer mastersizer, and infrared spectroscopy. No modification to the crystalinity and chemical structure of ibuprofen was observed. Dissolution of ibuprofen microparticles reached 100% in 3 minutes compared with less than 10% for unmodified ibuprofen. We concluded that both by the modification of formulation and the spray drying process it is possible to increase the dissolution rate of the tested model drug.

The rheology of wet powders: A measuring instrument, the compresso-rheometer

In order to control the mechanical properties and granulation processes of wet powders, steps were taken to design and develop a measuring instrument, the compresso-rheometer. Initial experiments were carried out on binary associations between microcrystalline cellulose powder and varying quantities of water.

Compaction behavior and deformation mechanism of directly compressible textured mannitol in a rotary tablet press simulator

Textured mannitol powder is widely used as a pharmaceutical excipient for tablet compaction. In order to choose the right tableting parameters, it is necessary to understand its mechanical behavior during deformation under industrial tableting conditions. The aim of this study was to evaluate the mechanical behavior during deformation of a textured mannitol using a rotary tablet press simulator. Mean yield pressure (Py) obtained by Heckel modeling, Walker coefficients (W) and Stress Rate Sensitivity (SRS) were compared to reference excipients, known for either their plastic (microcrystalline cellulose) or fragmentary (lactose and dibasic calcium phosphate) deformation behavior. Py, W and SRS values showed that the studied textured mannitol has a fragmentary deformation mechanism. Furthermore, this mechanical behavior was not sensitive to lubrication, which is characteristic of fragmentary excipients.

High-amylose sodium carboxymethyl starch matrices for oral, sustained drug release: development of a spray-drying manufacturing process

Context: High-amylose sodium carboxymethyl starch (HASCA) was recently proposed as a material for oral, sustained drug-release tablets prepared by direct compression. It was produced on a pilot scale, but appeared to be unsuitable for tableting and sustained drug release. Pilot-scale dry powder HASCA was dispersed in hot water and then precipitated with ethanol to give a dry powder presenting the required properties, but very high volumes of ethanol were used to recover the product. Objective: A process was therefore designed to transform totally amorphous pregelatinized HASCA by spray-drying into a suitable sustained drug-release excipient for matrix tablets while decreasing ethanol quantities. Results and discussion: During the first manufacturing step, that is, heating of the initial hydro-alcoholic suspension, powder and water concentrations are key parameters for the acquisition of excellent binding properties. Hence, a variable ratio of amylose Vh, a crystalline polymorph of amylose, to the amorphous form, is observed depending on the key parameter values. As the most crystalline samples give the weakest tablets, binding properties do not appear to be linked to the presence of a Vh form of amylose. On the other hand, a high water concentration results in excessive tablet strength, that is, inverse conditions leading to the appearance of a Vh form of amylose. Finally, variations in hydro-alcoholic composition appear to affect only tableting properties and do not influence the drug-release rate. Conclusion: A process designed to transform totally amorphous pregelatinized HASCA by spray-drying is proposed for easier, economical industrial HASCA production.

Definition of indices for the mechanical design of wet powders : application to the study of a natural polymer, microcrystalline cellulose

Abstract The formulation of a mixture for obtaining pellets by extrusion/spheronisation is based on experience and trials and not on a complete scientific understanding of the process. It has not been possible to exploit the progress made in rheology for characterizing the wet mixtures designed for use with this process. This is no doubt because of the difficulty of studying them by using existing rheometry apparatus in the traditional manner for substances possessing specific properties. For the essential conditions for conducting a conventional rheological study, i.e. the presence of a laminar flow with assumed perfect die wall adhesion, represents a difficult challenge to take up when working with heterogeneous materials whose density changes under the impact of pressure. This article is based on the use of an apparatus, the compresso-rheometer, which enables the extrusion process to be simulated on a reduced scale. It presents an original, precise study protocol resulting in mechanical characterisation through the use of two indices (visco-elasticity and plasticity) for microcrystalline cellulose/water mixtures. These new indices were established for the purpose of forecasting the behaviour of raw materials mixed with a liquid when subjected to a shaping process, and also for indirectly addressing the problems of formulation and dissolution.

Psychrometry as a methodological tool for optimizing the spray drying process.

Because psychrometry takes into account a great number of variables reflecting the quality of the drying air, it is an interesting tool to improve the control and the optimization of the spray drying process. In this article the authors study the evolution of the psychrometric variables according to the values taken by four inlet parameters (inlet air temperature, liquid flow rate, solid concentration of the spray dried liquid, and nature of the product). The results highlighted the existence of mathematical models making it possible to optimize the process, but also to underline the influence of the nature of the product on the drying mechanism.

Deformation behavior of crystallized mannitol during compression using a rotary tablet press simulator

Graphical abstract Figure. No caption available. ABSTRACT Mannitol is commonly used as a pharmaceutical excipient for tablets; the most widely used oral dosage form for drug delivery. For tableting, mannitol is provided in two different forms: native crystals and textured particles. In order to optimize its formulation, a good understanding of the mechanical behavior mechanism of mannitol is necessary. Thus, the aim of this study is to evaluate the deformation mechanism of native mannitol crystals presenting different particle sizes. Pharmaco‐technical and compression studies were performed using mannitol with different mean diameters (160 &mgr;m, 50 &mgr;m and 25 &mgr;m). Lactose (monohydrate) and microcrystalline cellulose were used as brittle and plastic reference materials, respectively. Tableting tests and mathematical models, HECKEL and WALKER, were used to study the deformation mechanism of mannitol (&bgr;). Mean Yield Pressure (Py) and WALKER coefficient (W) values showed that the studied crystalline mannitol presents a deformation mechanism close to brittle material. A particle‐size analyzer was used at different pulverization pressures to show the high sensibility of the mannitol particles to fragmentation when exposed to high pressures, especially for particles presenting 160 &mgr;m size. Scanning Electron Microscopy (SEM) was used to show the fragmentation after high‐pressure measurements.