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

Abstract The aim of the present study was to compare the dissolution rate and in-vivo biopharmaceutical performance of two polymorphic forms (form I & II) of ambrisentan (AMT) 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 (BFDH) method. Hirshfeld surface analysis maps and 2D fingerprint plots indicate a difference in shape index, curvedness and relative percent contribution of various contacts in both forms. Pre and post intrinsic dissolution compact studied by atomic force microscopy (AFM) 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 (IDR) than form I. Further, in-vivo pharmacokinetic study also showed significantly higher AUC0-24 and Cmax in form II compared to form I. Overall, this study demonstrates that form I & II of AMT exhibited the differential surface anisotropy which has significant implications on their biopharmaceutical performance.