Characterization and Stability of Amorphous Tadalafil and Four Crystalline Polymorphs

抄録

Tadalafil (TD), a phosphodiesterase-5 (PDE-5) inhibitor with poor oral bioavailability. The aim of the study was to prepare and characterize three crystalline polymorphs of TD (II, III, and IV) and the tadalafil amorphous form (TD-AM). TD polymorphs and TD-AM were prepared and characterized by polarized light microscope (PLM), scanning electron microscopy (SEM), differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), X-ray powder diffractometry (XRPD), and Fourier-transform (FT)IR, followed by the dissolution testing, physical stabilities and polymorphic transformation studies. TD-I and TD-II were found to be enantiotropically related, while TD-III was monotiotropically related to TD-I with heat release. Among all studied polymorphs, TD-AM demonstrated an extremely high intrinsic dissolution rate with most prolonged higher saturated concentration during dissolution, while TD-II, TD-III, and TD-IV converted to TD-I easily by supersaturation-mediated phase transformation. Upon heating under 60°C for 3 h and storing at long-term stability condition for 3 months, no phase transformation was detected for TD-I, TD-III, and TD-AM, while TD-II and TD-IV easily transformed to TD-I and TD-III, respectively. The higher intrinsic dissolution rate, prolonged supersaturated state during dissolution and favorable physical stability of TD-AM made it to be a very promising candidate for further product development.