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The pharmaceutical industry shows a current shift towards continuous production due to several advantages like reduction of production costs and time. The major challenge of continuous direct compression of tablets lies in the varying powder properties like flowability and tabletability. Fette Compacting has introduced a new tablet press for continuous direct compression. The big advantage of this tablet press is the introduction of a third compression roller, next to the two compression rollers for traditional pre- and main compression. This extra compression roller extends the dwell-time so tablets can be produced at high tableting speeds without loss in tablet hardness or other increasing tablet defects. In this study the influence of the third compression roller will be investigated using a powder, placebo S, which undergoes mainly fragmentation. Using an experimental design, the experiments are set up where the effect of varying tabletting speed and varying forces of the different rollers on the properties of the tablets is investigated. Results of tablet weight, hardness, thickness and their respectively relative standard deviations are analysed to investigate the potential of this third compression roller. Additionally, the powder is characterized by parameters like moisture content, density and particle size distribution. Results of powder characterization indicate a good flowing powder. Evaluation of results of the experimental design show that increasing the tableting speed has a negative influence on both hardness and weight of the tablets. However, results show that the placebo S formulation benefits from the third compression roller. The values of the applied forces on the different rollers, which give rise to the optimal tablet properties, are dependent on the varying tableting speed. Finally, a generic method concerning tablet hardness is generated. For this purpose, three additional powders with varying deformation properties are analysed. These powders are compared among each other and a generic method for the use of the third compression roller is generated.
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Monoclonal antibodies are becoming increasingly important in the pharmaceutical industry. The fact that they are required in such high concentrations in liquid formulations creates an even higher risk of aggregation of the antibodies. Aggregation substantially increases the risk of unwanted immunogenicity. Therefore, further research into the aggregation mechanisms is recommended. The aim of this master thesis is to better understand the influence of different excipients on the stability of an IgG4 monoclonal antibody. The chosen excipients were polyols (glycerol, erythritol, xylitol, sorbitol, maltitol, PEG300) and amino acids (L-arginine hydrochloride, L-lysine hydrochloride, L-glycine, L-proline, L-valine). These excipients were investigated in two buffers with different pH value. Mechanisms regarding the monoclonal antibody stability as well as the aggregation mechanisms are analyzed. The data obtained from the stability study at different temperatures (5, 30, 40 and 50 ° C) using size-exclusion chromatography (SEC) with in-line multi-angle light scattering (MALS) detection as well as dynamic light scattering (DLS) is used to to unravel and better understand the aggregation mechanisms. This data will be related to biophysical parameters including denaturation midpoint temperature (Tm) and aggregation temperature (Tagg), determined by differential scanning fluorimetry (DSF) and preferential interaction coefficient, measured by vapor pressure osmometry (VPO). A clear difference is seen between the effect of polyols and amino acids on stability, but also a difference in behavior of the excipients in the buffers with different pH value. The polyol formulations show a reduction in aggregation rates as their size increases. From a certain polyol size, sorbitol in this study, the aggregation rate remains more constant. No big differences in aggregation rate are seen between sorbitol and maltitol. The addition of basic amino acids causes a faster aggregation at higher temperatures. Compared to the aggregation rates of formulations containing L-arginine hydrochloride the formulations containing neutral amino acids with guanidine hydrochloride show a higher aggregation rate. Positive preferential interaction coefficients are determined between the protein and L-arginine hydrochloride, pH 4.6 and guanidine hydrochloride, pH 7.6 indicating preferential interaction between these excipients and the monoclonal antibody. Sorbitol, like the neutral amino acids L-glycine and L-proline, shows negative interaction coefficients at both pH’s. These negative coefficients show that the excipients are excluded from the protein surface. This indicates stabilization of the protein contrary to preferential interaction, which leads to destabilization.
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