Investigation of the tableting process in continuous production: influence of feeding and extended dwell time during compression on dependent process variables and tablet properties

Despite the high quantities of tablets produced daily, a lot of the established processes and formulations are the results of (suboptimal) trial-and-error experiments, contributing to the image that the entire field of pharmaceutical powder technology is more “an art than a science” [1]. Also, a large number of contributing papers to the field date from roughly two or three decades ago. Although the operation mode and press lay-out stayed basically unchanged since its invention, the instrumentation improved largely in terms of quality, accuracy and sensitivity. Moreover, due to the increased competition through generic manufacturing and the shift towards a more patient-centered production, more advanced tablet formulations exhibiting e.g. prolonged, extended, delayed or immediate release profiles have emerged. This, together with the Process Analytical Technology (PAT) – initiative, proposed by the American Food and Drug Administration (FDA) in 2004, encourages a shift towards a more scientifically based technology. The goal of the initiative is to stimulate the pharmaceutical industry to “design and develop processes that can consistently ensure a predefined quality at the end of the manufacturing process”. By identifying all sources of variation of importance for the product performance and quality, and by increased process understanding and continuous monitoring, quality could be built rather than tested into the product [2]. Together with the International Conference on Harmonization (ICH) Q8 guideline on Pharmaceutical Development, focusing on the Quality-by-Design (QbD) concept, it forms the regulatory framework to catalyze the shift of the pharmaceutical industry towards a redesigning of the current approach [3-5]. Seen in the light of these new movements within the tablet manufacturing area, it appears obvious that there is a need for new knowledge to fund a base for a thorough understanding of the continuous tableting process. This thesis aims to contribute in this large context by the investigation of the tableting process on a high-speed rotary tablet press. The goal was to increase the understanding of the influence of the properties of the starting material and process parameters on dependent process parameters and tablet properties. Since the PAT-initiative stimulates the introduction of new analytical tools to enhance process understanding and product quality, additional analytical chemistry tools, next to the built-in instrumentation were used. Moreover, due to the large amount of data obtained, Design of Experiments (DoE) and Multivariate Data Analysis (MVA) were administered to perform experiments and analyze data in a structured manner. Three main topics were addressed: - The role of the forced feeder: its influence on the properties of the starting material, on the die-filling process and on the final tablet properties. - The mechanism of (double) compression: its influence on dependent process parameters and on the final tablet properties. - The role of additional analytical chemistry tools in a continuous tableting process: its applicability to asses tablet properties, produced from starting material with different characteristics.