(466c) Development of New Screening Methodology for the Assessment of the Agglomeration Potential of APIs

Agglomeration of active pharmaceutical ingredients (API’s) in agitated filter driers (AFD) is a common occurrence on scale-up and is typically observed while the wet-cake is being stirred above a certain solvent composition. This can lead to snow-balling, excessive sticking, or simply cake hardening during the drying generating various forms of agglomerates. Agglomeration can impact downstream drug product manufacturing as well as bioavailability and in extreme cases can damage the agitator and/or lead to difficulty in removing the batch from the processing equipment, leading to significant material losses.

Therefore it is important to understand the risk of agglomeration potential prior to scale-up as early in development as possible. Mixer torque rheometry (MTR) has been shown in the literature to be a useful tool for studying the agglomeration potential for certain compounds. However, this methodology requires large quantities of API and we have recently demonstrated that in some cases under-predicts the agglomeration potential and does not account for cake hardening.

We have developed a simple screening protocol for assessing the agglomeration potential using resonant acoustic mixing, that minimizes the quantity of API used and can therefore be used early on in development. This methodology improves upon the MTR one as it allows for multiple conditions to be screened in parallel, saving time and in addition to a qualitative (visual) assessment, provides quantitative data after the material has been dried, thus assessing cake hardening as well. This methodology can also be used to assess the friability of the generated agglomerates. The development and reproducibility of this new methodology will be discussed as well as the impact of particle size, particle size distribution, solvent selection, and solvent loading on the agglomeration potential for several Takeda APIs. Finally, a comparison of this new method and the MTR method as well as a pilot plant validation of the revised drying conditions developed based on this new methodology will also be presented.