Entwicklung von Verfahren zur Herstellung von Pellets mit hoher Wirkstoffbeladung durch Pulverbeschichtung und Direktpelletierung in der Luftgleitschicht (English shop)

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The aim of this work was to develop, using prototypes, processes for the manufacture of drug-loaded pellets by powder layering and direct pelletisation in the guided fluidised bed, also referred to as the “air-glide layer” (Luftgleitschicht). To date, the manufacture of drug-loaded pellets in the air-glide layer has been carried out mainly in the form of coating starter cores with solutions or suspensions. Since these processes are time-consuming and cost-intensive for the manufacture of highly loaded drug pellets, powder layering and direct pelletisation processes represent economically attractive alternatives.

Using prototypes and model drug substances, suitable apparatus settings and process parameters as well as formulations were developed in order to produce pellets with a high drug content of 80 % or more. The processes were assessed with regard to the time required for their performance and the layering efficiency or yield.

At a satisfactory yield or layering efficiency, drug pellets with the same drug content could be manufactured by direct pelletisation of the drug substance in a considerably shorter time than by powder layering. In addition, an even higher drug content could be achieved by direct pelletisation of the drug substance. In both processes the process time was limited by the stickiness of the powder mixture and the homogeneity of the moisture distribution. In the powder layering process the maximum spray rate was additionally limited by the tendency of the particles to be coated to agglomerate, the flow properties of the powder mixture and the powder feed rate. A uniform distribution of the spray medium was important in the direct pelletisation process in order to avoid the formation of large agglomerates and the adhesion of moist powder to the rotor and to the inner walls of the container.

The directly pelletised and powder-layered pellets were investigated with regard to typical pellet properties such as particle size distribution, shape factors, crushing strength, content and dissolution behaviour. The crushing strength and the dissolution behaviour were comparable and the drug substance was homogeneously distributed in each case. Narrower particle size distributions and better shape factors were achieved with manufacture by powder layering.

Since drug pellets are frequently coated in a further process step, for example with a functional coating, it is advantageous to be able to carry out both the manufacture of the drug pellets and the functional coating in the same apparatus. It was therefore investigated to what extent the drug pellets produced with the aforementioned prototypes, and in particular the direct pelletisation apparatus, are suitable for the application of a functional coating. Pellets produced both by powder layering and by direct pelletisation could be successfully coated in a conventional air-glide layer apparatus. After minor adaptation of the process parameters, the coating process could also be carried out in the direct pelletisation apparatus, whereby an even higher coating efficiency was achieved and therefore a lower coating level was already sufficient to attain the functionality of the coating. It could thus be shown that the manufacture of highly loaded drug pellets by direct pelletisation and their functional coating is in principle possible in the same apparatus without modification.