RESUMEN
The purpose of this work was to develop a robust hot-melt extrusion and strand pelletization process for manufacturing pellets with an immediate release (IR) of a poorly water-soluble active pharmaceutical ingredient (API), nimodipine. The robustness of pharmaceutical continuous manufacturing processes and of its control strategy is vital for competitiveness to traditional batch-manufacturing. Therefore, first the sensitivity of product quality, process stability, and process monitoring tools to i) parameter changes due to control actions and ii) typical process deviations, i.e., feeding errors, was investigated in a design of experiments (DoE). Thereby, die melt pressure was found to be highly sensitive to composition deviations, i.e. a limiting factor for process stability. Especially critical were deviations to increased HPMC content, since it behaved as a filler in the melt. Pelletization, or pellet size and size distribution respectively, were found to be sensitive to an increased throughput, due to the resulting insufficient strand cooling before the pelletizer. API dissolution in contrast, was found to be robust across the entire investigated range of formulation and process settings. Second, a design space for the production of IR pellets for subsequent tableting was established, and finally, a technical control strategy was developed to ensure a robust process. Near-infrared (NIR) spectroscopy was applied to monitor API content and the sensitivity of the residence time distribution (RTD) was investigated by means of tracer measurements. NIR-based API content monitoring and RTD models for material tracking were found to be at risk after processing melt with high HPMC content, due to a lack of purging by less viscous formulation compositions.
