Continuous manufacturing of a pharmaceutical cream: Investigating continuous powder dispersing and residence time distribution (RTD).

Recently, an innovative continuous manufacturing technology for a pharmaceutical oral suspension was proposed, based on two consecutive mixing units. A limitation of this technology is the need to dissolve or disperse powder-based raw materials in a liquid via a batch step before continuous manufacturing. Therefore, the aim of the current study was to develop and investigate a method to introduce powders continuously into the existing equipment via the implementation of two upstream continuous unit operations: a powder feeder and powder dispersing unit. A pharmaceutical cream was selected as model formulation to demonstrate the flexibility of the continuous manufacturing technology towards different types of semi-solid and liquid formulations. The ability to continuously feed and disperse active pharmaceutical ingredient (API) using the proposed method was assessed via an experimental design, in which the impact of several process parameters of the powder dispersing unit on the API concentration (relative error (RE) and relative standard deviation (RSD)) was examined. A Raman spectroscopic method was developed to quantify the API concentration in-line after the powder dispersing step. The API concentration was independent of the process parameters and fell within the acceptance limits, except for two experimental runs where a deviating API concentration was observed. These results demonstrate that the continuous powder feeding and dispersing method was suitable, and that a completely continuous manufacturing system was obtained. To achieve raw material traceability and understanding the mixing behavior, the residence time distribution (RTD) of a tracer inside the continuous manufacturing equipment was determined using a colorimetric technique. The time required to remove all tracer from the powder dispersing unit operation was very long (1481 s) and therefore the volume inside this unit operation should be reduced by designing new equipment with smaller dimensions. At the two consecutive mixing units, the peak and mean residence time were influenced by throughput, whereas mixing speed in both mixing units had a significant impact on the degree of axial mixing. Finally, the continuously manufactured cream had a similar rheological behavior as the original batch-wise manufactured cream.