Wei Yuanfeng, Ling Yunni, Su Meiling, Qin Lei, Zhang Jianjun, Gao Yuan, Qian Shuai
School of Traditional Chinese Pharmacy, China Pharmaceutical University.
School of Pharmacy, China Pharmaceutical University.
Chem Pharm Bull (Tokyo). 2018;66(12):1114-1121. doi: 10.1248/cpb.c18-00450.
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.
他达拉非（TD）是一种口服生物利用度较差的磷酸二酯酶-5（PDE-5）抑制剂。本研究的目的是制备并表征TD的三种结晶多晶型物（II、III和IV）以及他达拉非无定形形式（TD-AM）。通过偏光显微镜（PLM）、扫描电子显微镜（SEM）、差示扫描量热法（DSC）、热重分析（TGA）、X射线粉末衍射法（XRPD）和傅里叶变换红外光谱（FT）IR对TD多晶型物和TD-AM进行制备和表征，随后进行溶出度测试、物理稳定性和多晶型转变研究。发现TD-I和TD-II呈对映异构关系，而TD-III与TD-I呈单向异构关系且有热释放。在所有研究的多晶型物中，TD-AM表现出极高的固有溶出速率，在溶出过程中具有最长时间的较高饱和浓度，而TD-II、TD-III和TD-IV通过过饱和介导的相转变容易转化为TD-I。在60°C下加热3小时并在长期稳定性条件下储存3个月后，未检测到TD-I、TD-III和TD-AM发生相转变，而TD-II和TD-IV分别容易转化为TD-I和TD-III。TD-AM较高的固有溶出速率、溶出过程中延长的过饱和状态以及良好的物理稳定性使其成为进一步产品开发的非常有前景的候选物。
