(65b) Quantitative Simulation of Tablet Compression and Hardness Test Processes Using Discrete Element Method

In the formulation development of solid dose drug product (DP), understanding on the influence of physical properties of drug substance (DS) and excipients is critical on quality control of DP. While empirical correlation has been widely applied in qualitative estimation of DP quality, potential risk to fail DP specifications still exists, especially in technical transfer and manufacture scale-up activities. It may result in significant waste of DS or serious quality issue on DP. In order to avoid risk of failure and save DS, modeling using Discrete Element Method (DEM) has been interest of formulation development and DP manufacture in decades. The main challenge was how to develop quantitative correlation so that DEM particles were accurately representative of behavior of pharmaceutical DS and excipients in various unit operations.

In this work, the development of quantitative powder compressibility platform was described. A powder flowability platform developed in the previous studies [1, 2] was applied to guarantee that the flow behavior of DEM particles was representative of pharmaceutical powder. Material properties such as particle size distribution, true density, and flowability were collected and applied into simulations. Detailed compression profile of pharmaceutical powder was collected using ESH Tablet Compaction Simulator by Huxley Bertram. Tablet hardness data was collected using HT-300 hardness tester by Key International and tensile strength was calculated based on tablet shape. Development of the compressibility platform was performed using the commercial DEM software Star CCM+^® v11.06 by Siemens and with processors of dual CPUs, Intel^® Xeon^® E52640 @ 2.50 GHz. The Walton Braun Hysteretic contact model and the Parallel Bonds Model (PBM) were involved to model plasticity of pharmaceutical powder and rigidity of compacted tablet, respectively. After development and optimization, the platform was applicable to simulate one compression module and one hardness test module within 48 hrs with setting of material properties similar to pharmaceutical powders.

Based on the developed platform, influence of different DEM parameters on powder compressibility was estimated. Results showed that the setting of particle size distribution and particle flowability had little influence on compression profile. On the other hand, compression profile was significantly impacted by the setting of particle porosity, Young’s modulus, and stiffness ratio, while tablet hardness was mainly determined by the setting of tensile strength in PBM. Quantitative correlation was then developed between DEM particles and example pharmaceutical powders by adjusting DEM particle material properties. It was observed that simulation matched experimental data well. Several case studies were made to demonstrate capability of the platform in different scenarios such as binary system, punch adhesion, shape of tooling etc. The studies showed potential benefits of the proposed simulation method in the pharmaceutical powder compression processes, such as save of DS and risk reduction of batch failure, especially when technical transfer and scale-up of solid dose manufacture were involved.

1. Gao Y, Quantitative Investigation on Segregation Phenomenon Using Discrete Element Method in Large Scale Pharmaceutical Manufacture Process, AIChE Annual Meeting, San Francisco CA, Nov 2016, paper 788e.

2. Gao Y, Chalasani S, Mittal B, Computational Modeling of Low Shear Blending Process Using Discrete Element Method, AIChE Annual Meeting, Salt Lake City UT, Nov 2015, paper 412e.