(328d) Beyond Brittle/Ductile Classification: Applying Proper Constitutive Mechanical Metrics to Understand the Compression Characteristics of Pharmaceutical Materials

Pharmaceutical tablet development is complex because of very different objectives, such as a target release profile of the active pharmaceutical ingredient (API), sufficient tablet mechanical strength to limit defects, manufacturability of the powder formulation, and commercial trade dress constraints (e.g., tablet dose strength vs. size requirements) that must be fulfilled. Often, factors that improve one objective can be detrimental to another. For example, a formulation comprising mostly diluents (excipients) may be favored from a manufacturability standpoint. However, it may not be suitable for delivering high doses when a tablet size limit exists. Tablet formulators, then, must be savvy about choosing the right ‘ingredients’ to optimize all aspects of a tablet.

A key tablet property, its mechanical strength, depends on the compression characteristics of each ingredient that comprises the tablet formulation during and after the tableting process. The tablet characteristic is often classified as ‘brittle’ or ‘ductile’ with an elastic/viscoelastic subcategory sometimes added. A ductile tablet is obviously preferred over a brittle one, though a naturally brittle API can still be formulated into a ductile tablet by choosing appropriate diluents. The characteristics of a ductile or brittle material, however, are often misconstrued in the pharmaceutical literature. This is a result of a classification system that’s built primarily from correlating the ‘in-die’ (i.e., during compression) data to out-of-die behaviors of a handful of model materials, e.g., microcrystalline cellulose (MCC) for ductile behavior; mannitol, lactose, and calcium phosphate for brittle behavior; and starch for elastic and viscoelastic behavior. Such a ‘one size fits all’ approach can subsequently lead to inaccurate classification of APIs, which, more often than not, behave very differently than the above-mentioned model materials.

This study compares the commonly reported mechanical metrics of two proprietary APIs and two classical model excipients: MCC and mannitol. We demonstrate that materials classified as ‘ductile’ by Heckel’s or Kawakita’s ‘standards’ may bond weakly and exhibit the breaking characteristics of a brittle material, meaning that the ductile/brittle behavior under pressure is not always related to the brittle/ductile behavior of the final tablet. In contrast, our data shows that it is possible for materials possessing a high Young’s modulus and residual die-wall pressure to break in a ductile manner, akin to compressed metal powders. For the materials studied here, the Hiestand brittle fracture index (BFI) appears to capture the breaking behavior accurately—materials that break in a ductile manner all have small BFIs. Our data further highlight the complexity of pharmaceutical products, in particular APIs, and the need to evaluate a set of mechanical metrics, instead of simplistic assignments of ductility or brittleness based on in-die compression quantities that describe nothing more than the material’s compressibility, to classify truly the compression characteristics of tablets.