(70df) An Investigation of Flow, Compactibility, Sticking Tendency and Content Uniformity of Direct Compression Formulations

Purpose: Direct compression (DC) is a simple process associated with advantages such as fewer unit operations and stability issues as well as the potential to achieve fast dissolution and good compactibility. However, this process is less frequently used, due not only to the fewer means to control the process, but also due to the lack of understanding of this process. In addition, systematic investigations of formulation issues related to segregation, flow, and sticking are not available. In this study, our goal is to systematically investigate the impact of particle size matching, excipient ratio and grade, bulk drug properties, and drug loading on formulation performance, gaining understanding about how to enhance the robustness of the DC formulation and its applications. Methods: Avicel/lactose and Avicle/A-tab based formulations were selected for this study. The effects of the excipients on the flowability, compactibility, and tablet friability and disintegration time were studied. Then various compounds and different particle sizes were formulated at different drug loadings to determine the effects of drug loading as well as bulk properties such as compactibility, flowability, sticking tendency and particle size on these formulations. The effect of mixing was also studied. The performance of the formulations is evaluated by powder flow, tablet hardness/friability, tablet disintegration, sticking tendency and content uniformity. Design of experiments (DOE) was employed to systematically and quantitatively assess the effects. Results: The proper selection of the excipient ratio and type is essential for a DC formulation, which affect the flow, compactibility, tablet friability and disintegration. Bulk drug properties had a strong impact on powder flowability, tablet hardness, and content uniformity. For example, a smaller drug size significantly improves the tablet CU compared to a larger drug size at low drug loadings. Additionally, processing conditions were found to significantly affect content uniformity and powder flowability. For instance, high shearing mixing markedly improved tablet CU, and in some cases, powder flow. Excipient selection also impacted powder and tablet properties. Conclusions: The bulk drug properties showed a strong effect on flowability, compactibility, and content uniformity. In particular, particle size selection was critical for flowability at high drug loadings and for content uniformity at low drug loadings. In cases where bulk drug properties limited formulation performance, optimization of processing conditions such as mixing and rational excipient selection improved content uniformity, tablet hardness, and flowability. By addressing a combination of formulation parameters, such as the excipient ratio and the mixing process, and bulk drug properties, such as particle size and flowability, the direct compression formulation and its operating window are greatly improved.