(655b) Establishing a Powder Characterization Workflow to Determine Ideal Process Parameters for a Vibratory Mixing Process

Blending of granular media can be deemed as one of the fundamental unit operations in the tablet manufacturing. The homogeneity of a powder blend does not only influence content uniformity in most process schemes, but also the proper function of all excipients being part of a drug product. The present study considers a process route where this issue is circumvented by design via dosing the ingredients for each tablet one after another into the tableting die prior to blending and compaction. Nevertheless, the homogeneity of the blend is crucial for obtaining a tablet exhibiting desired critical quality attributes (CQAs) like hardness or release characteristics. The abovementioned process route, i.e., single-tablet-scale direct compression¹ relies on a vibratory mixing process for blending small amounts (< 1g) of powder. While this process is fast and highly efficient for free-flowing to moderately cohesive powder systems, the process parameters for blending cohesive mixtures need to be picked with care. This study proposes a systematic approach to derive the ideal vibration parameters for blending via standardized shear cell experiments. The prediction workflow relies on a semi-mechanistic model which was derived based on high-speed imaging investigations of the powder bed in the mixing vessel which revealed the failure mechanism of the vibratory mixing process. High-speed imaging revealed that the high accelerations inherent to a fast vibratory mixing process lead to the formation of a densely packed layer, if the mixture contains a relevant amount of cohesive powder. If the strength of this layer exceeds the stresses imposed on it by the vibratory mixing process, it cannot be disrupted, which prevents the agitation of the powder bed. The semi-mechanistic model developed in this study predicts the strength of this powder layer based on the cohesivity of the ingredients, determined in shear cell experiments, and the compaction pressure imposed on the powder bed during the oscillatory motion of the mixing vessel. A similar approach which is used for determination of the compaction pressure is used to calculate the tensile stress emerging in the powder bed during oscillation, enabling the calculation of the operating window for this powder system. Together with information from previous studies of Kottlan et al.^2,3 , which suggest, that the within a range of 100-300 Hz, lower frequencies lead to faster mixing, the ideal frequency can be determined. Experimental validation with the cohesive excipients Sorbolac 400 and Vivapur 105 showed good correlation with the prediction. The formation of a stable layer was not observed at the frequencies suggested by the model, i.e., 120 Hz and 130 Hz respectively, enabling the mixing process for these cohesive excipients.

Hence, this study lays the basis for predicting reliable process parameters for small-scale vibratory mixing, while providing unprecedented insight to the complex behavior of cohesive powder in this very process.

References

1. Kottlan, A. et al. Single-tablet-scale direct-compression: An on-demand manufacturing route for personalized tablets. Int J Pharm 643, (2023).
2. Kottlan, A., Glasser, B. J. & Khinast, J. G. Vibratory mixing of pharmaceutical powders on a single-tablet-scale. Powder Technol 387, 385–395 (2021).
3. Kottlan, A., Glasser, B. J. & Khinast, J. G. Powder bed dynamics of a single-tablet-scale vibratory mixing process. Powder Technol 414, 118029 (2023).