Implication of Differential Surface Anisotropy on Biopharmaceutical Performance of Polymorphic Forms of Ambrisentan

The aim of the present study was to compare the dissolution rate and in vivo biopharmaceutical performance of 2 polymorphic forms (form I and II) of ambrisentan and correlate with their surface molecular environment. Dominance of various functionalities on the surface of specific crystal facets of both forms was predicted by Bravais-Friedel-Donnay-Harker method. Hirshfeld surface analysis maps and 2D fingerprint plots indicate a difference in shape index, curvedness, and relative percentage contribution of various contacts in both forms. Pre- and post-intrinsic dissolution compact studied by atomic force microscopy showed a significant difference in surface roughness and defects formation in form II as compared to form I which is attributed to the presence of more hydrophilic surfaces. The hydrophilic molecular surface environment of form II is ascribed to its improved intrinsic dissolution rate than form I. Furthermore, in vivo pharmacokinetic study also showed significantly higher AUC_0-24 and C_max in form II compared to form I. Overall, this study demonstrates that form I and II of ambrisentan exhibited the differential surface anisotropy which has significant implications on their biopharmaceutical performance.