Determination of microsphere solidification time in the solvent evaporation process.

The aim of this work was to define the time of microsphere solidification during the solvent evaporation process. Microspheres were prepared by the solvent evaporation method, using acetone/liquid paraffin solvent system, ketoprofen as a model drug and Eudragit RS as a matrix polymer. Two sets of experiments were performed--in the first one the initial temperature of the emulsion system was 5 degrees C and in the second one 25 degrees C. In each set, two batches of microspheres were compared at constant emulsion stirring rate 250 and 1000 rpm and intermediate batches where the emulsion stirring rate was lowered from 1000 to 250 rpm at pre-defined times after the beginning of the inner phase solvent evaporation. By comparison of the properties of these microspheres, an insight was obtained into the mechanism of microspheres formation. The criterion for determination of microsphere solidification time was the resemblance between the microsphere properties of the batches prepared by stirring rate change and the batch prepared by constant stirring at 1000 rpm. A stirring rate change after the solidification has no influence on microsphere properties, that means that they are the same as of the batch prepared by constant stirring at 1000 rpm. The results of the sieve analysis and particle size distribution of microspheres show that the time of microspheres solidification is in the interval between 15-20 min if the initial temperature is 5 degrees C and between 10-20 min if the initial temperature is 25 degrees C. From the release profiles of ketoprofen, one can infer that the times of solidification for both initial temperatures are a bit lower. The microscopic pictures, which enable one to follow the processes in the system, confirmed the result obtained by the sieve analysis. In spite of its inability to distinguish between single particles and agglomerates, the sieve analysis enabled one to determine the actual time of solidification, while the drug release determination was not sensitive enough to trace small differences in surface area due to particles aggregation.

The influence of stirring rate on biopharmaceutical properties of Eudragit RS microspheres.

Eudragit RS microspheres containing pipemidic acid, as a model drug, were prepared by the solvent evaporation method using an acetone/liquid paraffin solvent system. The aim of the work was to evaluate the influence of stirring rate on the average particle size, particle morphology, drug content and release kinetics, as well as the influence of particle size on microsphere morphology, drug content and release kinetics. Stirring rate has been found to significantly influence the average diameter of microspheres. The average diameter decreases as the stirring rate increases. This can be explained by production of a finer dispersion of droplets when higher stirring rates are applied and, consequently, by the formation of smaller microspheres. With increasing stirring rate and increasing fraction particle size the drug content also increases. It is assumed that this dependence is a consequence of an uneven diffusion of the drug from the inner to the outer emulsion phase, and an uneven encapsulation of drug particles during the preparation. Drug release follows the Higuchi model. As seen from SEM photographs, larger microspheres are more porous and the microspheres produced at higher stirring rates are more porous than those produced at lower stirring rates. This explains the unexpected finding that the release rate increases as the fraction particle size and the stirring rate increase.