Structural insights into mechanical anisotropy in ambrisentan polymorphs

Abstract

Mechanical properties of drug molecules largely affect pharmaceutical processing into a finished product. Structural insights together with computational prediction tools help develop a crystal engineering approach to modulate crystal mechanical parameters. This study focuses on mechanical anisotropy in ambrisentan polymorphs (form I and II). Nanoindentation experiments revealed higher hardness (H) and elastic modulus I of form I as compared to form II, while form II showed lower H/E (0.03) as compared to form I (0.08). These properties were rationalized based on the potential slip plane in form II, which exhibited relatively larger d-spacing and lack of hydrogen bonding interaction across plane. On the contrary, form I revealed the presence of an interlocked 3D clustering network that may retard the gliding of the slip planes under the indention stress. These features were found to be consistent with the predicted mechanical parameters. Besides, the energy framework calculation displays relatively higher interlayer energy in form I, which is attributed to the cohesive crystal lattice. However, in form II, a smaller number of intertwined cylinders resulted in a smaller energetic barrier for sliding molecular layer under applied load during the nanoindentation experiment. In addition, AFM studies have indicated higher surface roughness in form II pointing towards softer and less brittle crystal than form I responsible for ease of elasticity under external stress. Hence, in-depth knowledge of structural features together with mechanical properties helps to establish structure–mechanical property relationships. Overall, form II (metastable form) exhibited higher plasticity and good tabletability than form I, which is attributed to the differential crystal packing, slip systems, strength of intermolecular interactions, surface contacts, and surface roughness. The present study showcases the implications of the crystal structure anisotropy on the mechanical performances that would aid in the selection of the right solid form in formulation development.