(384f) Impact of Tooling Design during Development and Risk Evaluation of Tri-Layer Tablet Formulations

Multi-layer tablet is one of the formulation strategies utilized to mitigate chemical and/or physical incompatibility between different drug substances when delivering fixed dose combination drugs. Compressing multi-layer tablets has significant challenges because the interface(s) between neighboring layers are subject to defects such as delamination. It is therefore important to understand the factors that contribute to the strength of the interfaces. During early stages of drug development, feasibility studies are often conducted by making multi-layer compacts with round flat-faced tooling as the exact size and shape for the commercial tablets may not be finalized at that point. However, the link between different tooling designs and multi-layer tablet performance is not well established.
 
This study examines the major engineering considerations when using mini-piloting tools to gauge the risk of interfacial defects in a tri-layer tablet. The first layer (layer A) of the tri-layer tablet was a wet granulation formulation of 56% drug load. The middle layer (layer M) was the inert layer consisting of a placebo blend. The third layer (layer B) was a dry granulation formulation of 33% drug load. The impact of tablet weight and dimensions (diameter and thickness) were evaluated to gain understanding during scale up/down as needed in early feasibility assessment and in troubleshooting. The factors in tooling selection, including tablet shape (round vs. oval), cup depth (0 vs. 0.054�), and embossing (small vs. large), were evaluated to gain insight on the impact of tooling design on the interface strength of the tri-layer tablet. Tablets were compressed under different main compression forces while keeping the first and second layer tamping forces constant. Axial test was performed to quantify the interface strength under tensile stress.
 
The thickness, diameter, and aspect ratio of the tablet were found to have a profound impact on the interface strength at a given compression pressure and on the compression pressure under which the interface start to fail, causing tablet delamination. These were the results of combined factors of the compressibility of the individual layers, the force transmission through the layers during compression (effect of tablet thickness), and the ejection force (effect of aspect ratio). The presence of a 0.054� cup depth was found to lower the interface strength to less than 50% of that of a flat tablet. This cup depth effect is consistent with the observations made in the monolithic tablet regime and can be explained by the non-uniform density distribution caused by the curvature of the tablet interface. The oval shaped tablets were found to reduce the interface strength by 30 N or more compared to the round shaped tablets, suggesting that compacts made with round flat faced toolings may provide false positive results when used to assess the interface risks of a multi-layer tablet. Large embossing on the tooling appeared to help enhancing the interface strength, probably by providing more surface areas for the neighboring layers to interlock.
 
This study elucidates the effects of scale-related factors like tablet weight and dimensions on the interface strength of a tri-layer tablet. These effects, not previously well studied or even realized during development, can significantly impact the feasibility evaluation of a multi-layer tablet. It also highlights the importance of tooling design selection on the performance of a tri-layer tablet that must be accounted for when using minipiloting tools for accelerated development of fixed dose combination products.