(653b) Simple Experimental Methods to Calibrate DEM Input Parameters for Pharmaceutical Tablet Applications

Tablet is the most common dosage form for small molecule drugs. Tablets are typically made by compressing a blended formulation containing some active pharmaceutical ingredients using a series of punch and die sets installed on a rotary press. After the tablets are made, they are often subjected to additional processing and handling that may damage them, such as dedusting, coating, packaging, and transportation/distribution. To ensure that formulated tablets can ‘survive’ the above processes, formulators often test the tablet's friability during the tablet development stage. The industry standard for such a test is summarized in USP <1216>. However, it is important to note that existing experimental tests, that described in USP <1216> included, may not fully represent the actual circumstances tablets face during manufacturing and further downstream processing.

To address such a shortcoming, the pharmaceutical industry has increasingly relied on alternate approaches to better simulate factors leading to tablet wear. In recent years, the progressive switch from empirical-based development to model-based quality-by-design as applied to pharmaceutics has triggered the proliferation of the use of predictive numerical methods such as the discrete element method (DEM). This simulation technique allows for the analysis of granular materials, including powders and tablets, by treating them as individual particles. By utilizing DEM, it becomes possible to virtually predict tablet dynamics during processing. However, researchers face a significant challenge in calibrating the tablet properties used in these models.

Model calibration is the initial step in any DEM modeling study and typically involves simulating an experimental system. The particle parameters in the model are then systematically varied until the predicted bulk quantities match the experimental counterpart. Since DEM simulations tend to be computationally intensive, the experimental system used for this calibration exercise must ideally satisfy the following criteria: (1) it can be easily set up experimentally and numerically, (2) it does not involve too many particles, and (3) the bulk behavior of the particles/tablets produced by the system is strongly influence by the particle parameter.

This work presents a series of simple experimental tests meeting the above criteria specifically for calibrating the DEM particle parameters relevant to simulating bulk tablets and wear behaviors in common pharmaceutical operations. Ansys Rocky software package was used for the DEM simulations. The DEM model incorporates real tablet shapes (instead of some glued-spheres representations). A hysteretic linear spring model and a linear spring Coulomb limit model were used to compute, respectively, normal contact and tangential forces.

We focus on the calibration of two groups of DEM parameters. The first group includes internal parameters such as particle density, Young's modulus, and Poisson's ratio. The second group comprises parameters that describe material interactions, which encompass coefficients of restitution and the static and dynamic friction coefficients between one particle and another as well as between the particles and the solids boundaries.

The calibration methods are covered in detail, including a thorough evaluation of the significance of each test for the DEM parameters and their comparison with the experimental data. The accuracy of the calibrated parameters is demonstrated through validation experiments. We highlight which input parameters are important for accurate simulations of pharmaceutical applications such as coating or packaging and identify parameters of lesser importance. Lastly, we describe the limitations of existing experimental methods for assessing tablet friability (e.g. the USP <1216> method) and propose alternative numerical approaches that can better predict tablet wear in a given pharmaceutical process.