Challenges and Opportunities in Optimizing Mechanical Properties of Drugs by Incorporating Excipients

Prof. Calvin Changquan Sun
Professor, Director of Graduate Studies, and Associate Department Head, Department of Pharmaceutics
University of Minnesota

Key Words: Flowability, tabletability, punch sticking, crystal engineering, particle engineering

Purpose: The manufacturing of high quality tablets requires certain powder mechanical properties, which are often not exhibited by drug substances. Common problems during tablet development include poor flowability, low tabletability, and punch sticking. The ability of traditional approaches of formulation screening and process control in addressing these problems are often limited. In contrast, crystal and particle engineering can address such challenges more effectively by designing drug-excipient composites with unique structures and desired properties.

Methods: Coating a small amount of discrete layer of nano guest particles on fine drug particles profoundly reduces cohesion of a powder,1 which significantly improves powder flowability.2 This flow-enhancing technique is broadly applicable because it is based on the particle contact physics that reliably reduces cohesion of a powder. Nano-coating can be attained using economical and continuous processes suitable for pharmaceutical manufacturing, such as comilling.3 The problem of poor tabletability of drugs is usually caused by insufficient areas of bonding among drug particles, due to the limited extent of permanent deformation of particles during the compression process.4 Accordingly, there is the opportunity for overcoming the poor tabletability problem by forming drug-excipient composite particles capable of forming a sufficiently large bonding area by compression. This can be achieved by 1) coating drug particle with a layer of deformable polymer,5 2) increasing plasticity of drug crystals through modifying crystal structure by incorporating in crystal lattice a pharmaceutically acceptable excipient, such as water and other coformers.6, 7 In addition, crystalline drug-excipient composites can modulate punch sticking propensity through modifying both mechanical properties and surface functional groups of drug crystal.8

Results: The discussion of fundamental materials science underlying each problem lays a foundation for identifying extremely effective crystal and particle engineering strategies for preparing drug-excipient composites. Such engineered drug particles exhibit optimal structures and properties, which subsequently lead to robust manufacturing of high quality tablet products.

Conclusion: The concept of Materials Science Tetrahedron is the main thread of this presentation.9 It guides effective API engineering to attain optimal properties, beyond these discussed here, to overcome problems and enable successful drug product development.


1. Kendall, K. Adhesion: Molecules and mechanics. Science 1994, 263, 1720-1725.

2. Yang, J.; Sliva, A.; Banerjee, A.; Dave, R. N.; Pfeffer, R. Dry particle coating for improving the flowability of cohesive powders Powder Technol. 2005, 158, 21-33.

3. Chattoraj, S.; Shi, L.; Sun, C. C. Profoundly improving flow properties of a cohesive cellulose powder by surface coating with nano‐silica through comilling. J. Pharm. Sci. 2011, 100, (11), 4943-4952.

4. Sun, C. C. Decoding Powder Tabletability: Roles of Particle Adhesion and Plasticity. Journal of Adhesion Science and Technology 2011, 25, (4-5), 483-499.

5. Shi, L.; Sun, C. C. Transforming powder mechanical properties by core/shell structure: Compressible sand. J. Pharm. Sci. 2010, 99, (11), 4458-4462.

6. Sun, C. C.; Hou, H. Improving mechanical properties of caffeine and methyl gallate crystals by cocrystallization Crystal Growth & Design 2008, 8, (5), 1575-1579.

7. Hu, S.; Mishra, M. K.; Sun, C. C. Twistable Pharmaceutical Crystal Exhibiting Exceptional Plasticity and Tabletability. Chem. Mater. 2019, 31, (10), 3818-3822.

8. Paul, S.; Wang, C.; Wang, K.; Sun, C. C. Reduced Punch Sticking Propensity of Acesulfame by Salt Formation: Role of Crystal Mechanical Property and Surface Chemistry. Molecular Pharmaceutics 2019.

9. Sun, C. C. Materials science tetrahedron—A useful tool for pharmaceutical research and development. J. Pharm. Sci. 2009, 98, (5), 1671-1687.