Abstract
The manufacturing of the majority of solid oral dosage forms is based on the densification of powder. A good understanding of the powder behavior is therefore essential to assure high quality drug products. This is particularly relevant for the capsule filling process, where the powder bulk density plays an important role in controlling the fill weight and weight variability of the final product. In this study we present a novel approach to quantitatively measure bulk density variations in a rotating container by means of terahertz reflection technology. The terahertz reflection probe was used to measure the powder density using an experimental setup that mimics a lab-scale capsule filling machine including a static sampling tool. Three different grades of α-lactose monohydrate excipients specially designed for inhalation application were systematically investigated at five compression stages. Relative densities predicted from terahertz reflection measurements were correlated to off-line weight measurements of the collected filled capsules. The predictions and the measured weights of the powder in the capsules were in excellent agreement, where the relative density measurements of Lactohale 200 showed the strongest correlation with the respective fill weight (R2=0.995). We also studied how the density uniformity of the powder bed was impacted by the dosing process and the subsequent filling of the holes (with excipient powder), which were introduced in the powder bed after the dosing step. Even though the holes seemed to be filled with new powder (by visual inspection), the relative density in these specific segments were found to clearly differ from the undisturbed powder bed state prior to dosing. The results demonstrate that it is feasible to analyze powder density variations in a rotating container by means of terahertz reflection measurements and to predict the fill weight of collected capsules.
Highlights
Powder bulk properties are known to be crucial for the operation of many pharmaceutical processes and the quality of final products, such as tablets and capsules
A good understanding of the powder behavior is essential to assure high quality drug products. This is relevant for the capsule filling process, where the powder bulk density plays an important role in controlling the fill weight and weight variability of the final product
We demonstrated the applicability of the terahertz technology as a new process analyzer to determine powder bulk density variations in a moving powder bed
Summary
Powder bulk properties are known to be crucial for the operation of many pharmaceutical processes and the quality of final products, such as tablets and capsules. Powder density variations may impact tablet mass and hardness, as well as the dissolution performance, affecting patients (Singh et al, 2015). Capsules are typically filled with powder or pellets. First of all, filling processes are typically volumetric, i.e., a certain volume of powder is filled into capsules. Only if the density remains constant throughout the process the same mass is filled in every capsule. The fill weight is considered to be directly related to the drug content. Since this requires a uniform blend, both the fill weight variability and content uniformity are critical quality attributes (CQAs) as defined within the Quality-by-Design (QbD) framework (Faulhammer et al, 2014b)
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