AbstractsEngineering

The manufacturing of the most common pharmaceutical dosage forms, tablets, requires good mass flowability and uniform particle size distribution. Granulation is often needed to improve these properties prior to tablet compression. Thus, rapid methods for analysing the key powder and granule properties, such as particle size, flowability and moisture content are needed. Until recently, the development and control of pharmaceutical unit operations was based on an empirical approach rather than process understanding. To be able to build quality into the products, improved understanding of materials and processing is needed. This can be reached by developing complementary automated analytical methods that are suitable for continuous on-line or in-line process monitoring. The aim of this thesis was to investigate whether modern analytical tools can provide rapid and reliable real-time insight into powder performance during solid dosage form processing. The first study evaluated the impact of paracetamol loading and the physical characteristics of powders on the flowability of microcrystalline cellulose and paracetamol mixtures. A novel small-scale flow device proved to be suitable for rapid flowability screening of different formulations. Particle size distribution and drug loading had the largest impact on the flowability. The main focus of this thesis was on the utilisation of image analysis, near infrared (NIR) spectrocopy and process measurements as complementary process analytical tools during granulation. In addition to particle size distribution, the images revealed batch specific granule growth and attrition behaviour in real time. The changes in granule size were clearly linked to the continuously measured process conditions. Moreover, changes in image brightness during drying reflected the removal of water from the granules. The continuous moisture measurements based on process air moisture content and NIR spectroscopy provided real time information on the moisture content as well as the batch moisture profile during processing. The comparison of the methods also enabled the evaluation of the location of water in the process. The combination of on-line photometric imaging and near-infrared spectroscopy with continuous in-line process measurements facilitated continuous evaluation of key product properties during fluid bed granulation and provided insight into batch performance. The powder characterisation and process analytical technology (PAT) tools applied in this work enabled rapid and non-destructive determination of key powder and granule quality attributes. Even small changes in the material properties during processing were detected using the continuous and complementary process analytical measurements. Yleisimmän lääkemuodon, tabletin, valmistus edellyttää tabletoitavan jauheseoksen hyvää valuvuutta ja sopivaa hiukkaskokoa. Tabletointiin sopivien ominaisuuksien saavuttamiseksi raaka-aineet on useimmiten rakeistettava. Laadukkaiden lääkevalmisteiden suunnittelu edellyttää lisäksi entistä parempaa…