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Beyond Brittle/Ductile Classification: Applying Proper Constitutive Mechanical Metrics to Understand the Compression Characteristics of Pharmaceutical Materials.

Authors
  • Yost, Edward1
  • Mazel, Vincent2
  • Sluga, Kellie K1
  • Nagapudi, Karthik1
  • Muliadi, Ariel R3
  • 1 Small Molecule Pharmaceutics, Genentech, Inc., One DNA Way, South San Francisco, California 94080, USA.
  • 2 Univ. Bordeaux, CNRS, Arts et Metiers Institute of Technology, Bordeaux INP, INRAE, I2M Bordeaux, F-33400 Talence, France. , (France)
  • 3 Small Molecule Pharmaceutics, Genentech, Inc., One DNA Way, South San Francisco, California 94080, USA. Electronic address: [email protected]
Type
Published Article
Journal
Journal of Pharmaceutical Sciences
Publisher
Elsevier
Publication Date
Jul 01, 2022
Volume
111
Issue
7
Pages
1984–1991
Identifiers
DOI: 10.1016/j.xphs.2022.01.004
PMID: 35007567
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Active pharmaceutical ingredients (API) and excipients are often classified as 'brittle' or 'ductile' based on their yield pressure determined through the Heckel analysis. Such a brittle/ductile classification is often correlated to some measure of elasticity, die-wall stresses, and brittle fracture propensities from studies performed with a handful of model excipients. This subsequently gives rise to the presumption that all ductile materials behave similarly to microcrystalline cellulose (MCC) and that all brittle materials to lactose, mannitol, or dicalcium phosphate. Such a 'one-size-fits-all' approach can subsequently lead to inaccurate classification of APIs, which often behave very differently than these model excipients. This study compares the commonly reported mechanical metrics of two proprietary APIs and two classical model excipients. We demonstrate that materials classified as 'ductile' by Heckel's 'standards' may behave very differently than MCC and in some cases may even have a propensity for brittle failure. Our data highlight the complexity of APIs and the need to evaluate a set of mechanical metrics, instead of binary assignments of ductility or brittleness based on quantities that do not fully capture the tableting process, to truly optimize a tablet formulation as part of the overall target product profile. Copyright © 2022 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.

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