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Experimental and Numerical Analysis of Stress Generation In Non-Circular Pharmaceutical Tablets - a Manufacturing Case Study

Stephen L. Conway1, Adam Procopio2, Marty J. Smith3, and Michael Gentzler1. (1) Center for Material Science and Engineering, Merck & Co., Inc., WP75B-210, PO Box 4, West Point, PA 19486, (2) Materials Characterization & Technology Assessment, Merck & Co., Inc., WP75B-210, PO Box 4, West Point, PA 19486, (3) Pharmaceutical Operations, Merck & Co., Inc., WP69-2, PO Box 4, West Point, PA 19486

A detailed understanding of the evolution of mechanical stresses in pharmaceutical tablets is critical in achieving product performance requirements, development of appropriate process control strategies, and in reducing manufacturing variability. Extensive literature exists to describe the rigorous solution of stress fields in simplified tablet geometries (most commonly, circular, flat-faced tablets), but considerably less addresses the complex tablet shapes of marketed pharmaceutical products.

Experimental and numerical results are presented for the case of a pharmaceutical product manufactured by compressing lubricated granulation in rotary tablet presses. We investigate potential causes of increased compression force requirements in full-scale manufacture, leading to premature punch tool wear. After verification that lubricant maldistribution is an unlikely cause of tensile strength depression (via NIR methods) we explore differences in tablet hardness control between two product images of differing shape. Combining instrumented hydraulic compaction simulation and hardness test data from the laboratory with two-dimensional finite element method (FEM) numerical simulations, a coherent representation of tensile stress generation and failure modes for the two tablet images is developed. Qualitative agreement between laboratory observations and FEM simulations of diametrical compression simulations is achieved. By scaling intrinsic tensile strength data developed for circular tablets, the effectiveness of varying compression force to control tablet hardness in the two manufacturing processes is determined. The analysis illustrates why compression of one image may struggle to meet existing hardness specifications readily achieved for another tablet shape. We find that the established hardness test methods for the two tablet images are not equivalent and cause significant diversions in principle stress fields and their temporal development.

Extending the FEM simulations enables the virtual testing of a modified tablet hardness test apparatus. Maximum principle stress development is examined for several options and designs evolve to avoid tablet pivoting, excessive bending moments, or localized tensile stresses at the tablet edge. A simple modification to the tablet testing apparatus is fabricated and confirmed to provide greater equivalency between the two tablet shapes. Contributors to test variability are considered. Revalidation of the manufacturing process is expected to confirm that tablet hardness specifications can be met with reduced compression forces, with no impact on tablet appearance, friability and dissolution. Greater consistency between tablet images is predicted, along with more effective exploitation of press-force adjustments as a process control variable. While extensions to the FEM simulation approach are proposed to enhance quantitative accuracy, the utility of fit-for-purpose FEM techniques in a pharmaceutical manufacturing setting is demonstrated.