(M1430-02-11) Fast and Efficient Development of a DC Formulation of Ondansetron Tablets Guided by a Digital Tool

Purpose: Direct compression (DC) is a widely used tablet manufacturing technique due to its simplicity and cost-effectiveness. Despite recent progress, DC formulation development remains largely empirical, making it still time-consuming and resource intensive. The integration of digital design tools into pharmaceutical development offers a promising alternative to conventional methods. In this study, we employed ZoomLab®, a digital tool to predict and guide the DC formulation development of ondansetron (ODS) tablets.

Methods: To predict manufacturability of a hypothetical DC formulation using ZoomLab®, the following properties of the ODS were needed: angle of repose (AoR, °); particle size distribution (d10, d50, d90, PSD, µm); true density (g/cm³); bulk density (g/cm³); tapped density (g/cm³), breaking force (N) of 3 tablets prepared at 3 compaction forces (kN), tablet weight (mg), diameter (mm), and thickness (mm). Based on such information, along with the properties of pure excipients of interest provided by the ZoomLab® database, the maximum API loading in a blend suitable for DC process could be predicted by assuming a linear relationship based on the processability of the powder blend. A 0-10 composite score, where 0 means “insufficient” and 10 means “excellent”; 5 is the acceptance value, was used for the process evaluation, taking into account the PSD, powder density, flowability, and tabletability properties of the predicted blend. The ZoomLab® predicted formulation was then prepared and characterized, including tabletability, flowability (Flow function coefficient, FFC; Compressibility index, CI; and AoR), and ejection force (EF, N). Kollitab® (DC 87 L, BASF), a coprocessed multifunctional excipient containing filler, binder, disintegrant and lubricant, was selected to streamline formulation efforts. The “score and corresponding values for each property“ of a binary mixture between the API and Kollitab® was predicted. To ensure successful high-speed tableting, we further optimized the formulation by following these critical attributes: 1) tablet tensile strength > 2 MPa, 2) flowability of the mixture better than Avicel PH102 (MCC), which represents the minimum acceptable flowability for high speed tableting, and 3) tablet EF < 600 N (EF was not predicted by ZoomLab®). Finally, the optimum formulation was subjected to friability and disintegration time (DT) tests.

Results: Pure ODS exhibited acceptable tabletability ( > 2 MPa within the practical compaction pressure range up to 350 MPa, Figure 1), but poor flowability (Table 1, worse than Avicel PH102). The maximum API loading formulation predicted by ZoomLab® was ODS (61%) and Kollitab® (39%), which was experimentally confirmed to exhibit acceptable tabletability and significantly improved flowability.  However, the flowability of this formulation was still poorer than the MCC. Additionally, EFs were higher than 600 N (Figure 1b).  Hence, we reduced the API percentage and added lubricant (sodium stearyl fumarate, SSF, Pruv®) to improve its processability. The final formulation that meets the prescribed manufacturability criteria was ODS (51%), Kollitab® (48%), and SSF (1%). Our data suggested that reducing the API percentage did not significantly impact tabletability, likely due to the similar compaction properties of the API and Kollitab® (Figure 1). With decreasing API percentage, flowability increased and EF decreased, particularly with the inclusion of SSF. For the final formulation, compaction pressure at ~65 MPa was found to be sufficient for making tablets with friability < 0.8%.  Subsequently, we prepared a batch of tablets at this pressure and confirmed that their DT, tablet weight variation, and friability met the corresponding USP criteria.

Conclusion: In this work, ZoomLab® was successfully applied to expedite the development of an ODS DC formulation with a 51% API loading. This high API loading is generally not expected for DC formulation and a trial-and-error formulation approach will likely start from a much lower drug loading, requiring more experimental data. The high API loading formulation (61%) initially predicted by the digital tool was possible due to the outstanding flowability and compressibility of Kollitab®.  This established an excellent starting point for the formulation screening.  Subsequently, only minor formulation modifications were needed to ensure manufacturability and tablet performance, leading to efficient drug development.

Acknowledgements: We acknowledge the full financial support for this project provided by BASF Corporation. C.C.S thanks the National Science Foundation for support through the Industry University Collaborative Research Center grant IIP-2137264, Center for Integrated Materials Science and Engineering for Pharmaceutical Products (CIMSEPP).

Figure 1. a) Tabletability and b) ejection force profiles of the powders and blends

Table 1. Flowability of the powders and blends