Bernard Bataille

Development of spray-dried acetaminophen microparticles using experimental designs

Experimental factorial designs were built to investigate the effects of five parameters on production yields and moisture contents of spray-dried products. These factors concerned both the solution feed (drug concentration, colloidal silica concentration and polymer/drug ratio) and the spray dryer (inlet temperature and feed rate). Three formulations containing cellulose derivatives and acetaminophen were tested. The aim of the study was to optimize the operating conditions to maximize production yields while minimizing moisture contents. First screening experiments consisting of fractional factorial designs revealed the most significant factors to be inlet temperature, feed rate and their interaction for both formulations containing sodium carboxymethylcellulose and feed rate and colloidal silica concentration for the formulation containing microcrystalline cellulose. Then, the optimal operating conditions were estimated by response surface methodology. Central rotational composite designs showed quadratic models were adequate. New assays were carried out using these last conditions to evaluate both the repeatability and reproducibility of the spray-drying technique. Yields above 80% and moisture content of approximately 1% were reached. The characterization of microparticles revealed the poor flowability of the spray-dried products due to significant cohesiveness and very small size (less than 55 microm).

Factorial design in the feasibility of producing Microcel MC 101 pellets by extrusion/spheronization

Abstract This study evaluates the effects of certain process variables in the feasibility of producing Microcel MC 101 pellets by the extrusion/spheronization technique. A 2 3 factorial design was realised to demonstrate the influence of the significant factors and their interactions in the experimental response. The selected process variables such as water content, extruder screen size and spheronizer speed were studied, as well as their influences on the properties of particle size distribution and the densities were determined. The results showed that high levels of the three factors increased sphere size, and low levels decreased it. A strong interaction between water content and extruder screen size is observed for the particle size distribution response. Extruder screen size has a significant effect on the bulk density. Water content and spheronizer speed interaction influence the sphere density.

High-amylose sodium carboxymethyl starch matrices for oral, sustained drug-release: formulation aspects and in vitro drug-release evaluation.

High-amylose sodium carboxymethyl starch (HASCA), produced by spray-drying (SD), was previously shown to have interesting properties as a promising pharmaceutical sustained drug-release tablet excipient for direct compression, including ease of manufacture and high crushing strength. This study describes the effects of some important formulation parameters, such as compression force (CF), tablet weight (TW), drug-loading and electrolyte particle size, on acetaminophen-release performances from sustained drug-release matrix tablets based on HASCA. An interesting linear relationship between TW and release time was observed for a typical formulation of the system consisting of 40% (w/w) acetaminophen as model drug and 27.5% NaCl as model electrolyte dry-mixed with HASCA. Application of the Peppas and Sahlin model gave a better understanding of the mechanisms involved in drug-release from the HASCA matrix system, which is mainly controlled by surface gel layer formation. Indeed, augmenting TW increased the contribution of the diffusion mechanism. CFs ranging from 1 to 2.5 tonnes/cm(2) had no significant influence on the release properties of tablets weighing 400 or 600 mg. NaCl particle size did not affect the acetaminophen-release profile. Finally, these results prove that the new SD process developed for HASCA manufacture is suitable for obtaining similar-quality HASCA in terms of release and compression performances.

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.

Estimation of the percolation thresholds in ternary lobenzarit disodium–dextran–HPMC hydrophilic matrices tablets: Effects of initial porosity

The aim of this work is to estimate the excipient percolation threshold for a new combined matrix native dextran (DT), series B110-1-2 (Mw 2 x 10(6)): HPMC K4M CR: lobenzarit disodium (LBD) system and demonstrate the advantages of this ternary system with respect to previously reported binary dextran:LBD and HPMC:LBD tablets. The formulations studied were prepared with different amounts of excipient (DT:HPMC, 4:1 (wt/wt) for all tablets and relative polymer/drug particle size of 4.17) in the range of 10-70% (wt/wt). Dissolution studies were carried out using the paddle method (100 rpm) and one face water uptake measurements were performed using a modified Enslin apparatus. The Higuchis models as well as the non-linear regression were employed as empiric methods to study the released data. Values of diffusion exponent 0.588<n<0.784 (Korsmeyer equation) for dissolution profile and water uptake mechanism 0.715<n<0.960 (Davidson and Peppas equation) suggests anomalous or complex mechanisms in all cases. The critical points in ternary tablets were reduced from 44.75% (v/v) of excipient (correspond to purely native dextran) to 22.34% (v/v) (corresponding to mixture native dextran:HPMC, 4:1, wt/wt). The initial porosity (IP) of hydrophilic matrices above the values of 20% has an important influence on the percolation threshold as well as on establishment of the gel barrier responsible for the controlled release from the DT:HPMC:LBD tablets.

Estimation of the percolation thresholds in lobenzarit disodium native dextran matrix tablets

The objective of the present work is to estimate for the first time the percolation threshold of a new series of dextran (native dextran of high molecular weight [B110-1-2, Mw=2×106]), in matrices of lobenzarit disodium (LBD) and to apply the obtained result to the design of hydrophilic matrices for the controlled delivery of this drug. The formulations studied were prepared with different amounts of excipient in the range of 20% to 70% wt/wt. Dissolution studies were performed using the paddle method (100 rpm) and one face water uptake measurements were performed using a modified Enslin apparatus. The Higuchi, zero-order, and Hixson-Crowell models as well as the nonlinear regression model were employed as empiric methods to study the release data. Values of diffusion exponent 0.563<n<0.786 (Korsmeyer equation) for dissolution profile and water uptake mechanism 0.715<n<1 (Davidson and Peppas equation) suggested anomalous or complex mechanisms. On the other hand, the contribution of the relaxation or erosion and of the diffusive mechanism in Peppas-Sahlin equation indicated that the main mechanism for drug delivery from tablets is swelling controlled delivery (Kr/Kd<1). The critical points observed in kinetic parameters above 58.63% vol/vol of native dextran B110-1-2 plus initial porosity in the LBD-dextran matrices with a relative polymer/drug particle size of 4.17 were attributed to the existence of an excipient percolation threshold.

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.

Spray-dried solid dispersions of nifedipine and vinylcaprolactam/vinylacetate/PEG6000 for compacted oral formulations

The aim of this work was to investigate an alternative processing technology for a new polymeric solubilizer used mainly in hot melt extrusion. Poorly soluble nifedipine was co-processed through spray-drying with poly(vinyl caprolactam-co-vinyl acetate-co-ethylene glycol) (PVCVAEG) in different ratios. The resulting spray-dried powders were formulated and compacted into tablets forms. Spray drying produced reduced smooth spherical particles with PVCVAEG and more rough surfaces without PVCVAEG. Crystallinity of the co-processed nifedipine with the polymeric solubilizer was reduced. Plasticization of the polymeric solubilizer was observed with increasing drug content. Diffraction patterns in the small angle region as well as transmission electron microscopy showed results supporting phase separation throughout the spray dried particles of high drug content. Compaction with PVCVAEG improved cohesiveness of spray-dried compacts. Heckel modeling showed that deformation of PVCVAEG containing powders was more plastic compared than brittle nifedipine powders. Dissolution kinetics of all spray-dried samples was improved compared to original nifedipine crystals. Co-processed nifedipine with PVCVAEG did not show improved dissolution rate when compared to spray drying nifedipine alone. All though PVCVAEG is more commonly co-processed with drugs by hot melt extrusion to produce solid dispersions, the results show that it also can be processed by spray drying to produce solid dispersions. PVCVAEG improved compactibility of formulated spray dried powders.