Wlodarski K, Sawicki W, Haber K, Knapik J, Wojnarowska Z, Paluch M, Lepek P, Hawelek L, Tajber L
Medical University of Gdansk, Department of Physical Chemistry, Hallera 107, 80-416 Gdansk, Poland.
Medical University of Gdansk, Department of Physical Chemistry, Hallera 107, 80-416 Gdansk, Poland.
Eur J Pharm Biopharm. 2015 Aug;94:106-15. doi: 10.1016/j.ejpb.2015.04.031. Epub 2015 May 19.
To improve solubility of tadalafil (Td), a poorly soluble drug substance (3μg/ml) belonging to the II class of the Biopharmaceutical Classification System, its six different solid dispersions (1:1, w/w) in the following polymers: HPMC, MC, PVP, PVP-VA, Kollicoat IR and Soluplus were successfully produced by freeze-drying. Scanning electron microscopy showed a morphological structure of solid dispersions typical of lyophilisates. Apparent solubility and intrinsic dissolution rate studies revealed the greatest, a 16-fold, increase in drug solubility (50μg/ml) and a significant, 20-fold, dissolution rate enhancement for the Td/PVP-VA solid dispersion in comparison with crystalline Td. However, the longest duration of the supersaturation state in water (27μg/ml) over 24h was observed for the Td solid dispersion in HPMC. The improved dissolution of Td from Td/PVP-VA was confirmed in the standard dissolution test of capsules filled with solid dispersions. Powder X-ray diffraction and thermal analysis showed the amorphous nature of these binary systems and indicated the existence of dispersion at the molecular level and its supersaturated character, respectively. Nevertheless, as evidenced by film casting, the greatest ability to dissolve Td in polymer was determined for PVP-VA. The crystallization tendency of Td dispersed in Kollicoat IR could be explained by the low Tg (113°C) of the solid dispersion and the highest difference in Hansen solubility parameters (6.8MPa(0.5)) between Td and the polymer, although this relationship was not satisfied for the partially crystalline dispersion in PVP. Similarly, no correlation was found between the strength of hydrogen bonds investigated using infrared spectroscopy and the physical stability of solid dispersions or the level of supersaturation in aqueous solution.
为提高他达拉非（Td）的溶解度，他达拉非是一种属于生物药剂学分类系统II类的难溶性药物（溶解度为3μg/ml），通过冷冻干燥成功制备了其在以下聚合物中的六种不同的固体分散体（1:1，w/w）：羟丙甲纤维素（HPMC）、甲基纤维素（MC）、聚乙烯吡咯烷酮（PVP）、聚乙烯吡咯烷酮-醋酸乙烯酯共聚物（PVP-VA）、聚丙烯酸树脂IR（Kollicoat IR）和固体分散体聚合物（Soluplus）。扫描电子显微镜显示出冻干物典型的固体分散体形态结构。表观溶解度和固有溶解速率研究表明，与结晶态Td相比，Td/PVP-VA固体分散体的药物溶解度提高幅度最大，增加了16倍（达到50μg/ml），溶解速率显著提高，增强了20倍。然而，在羟丙甲纤维素中的Td固体分散体在24小时内观察到在水中（27μg/ml）的过饱和状态持续时间最长。在填充固体分散体的胶囊的标准溶出度试验中证实了Td从Td/PVP-VA中的溶出度得到改善。粉末X射线衍射和热分析表明这些二元体系具有无定形性质，分别表明在分子水平上存在分散及其过饱和特性。尽管如此，通过流延成膜证明，对于聚乙烯吡咯烷酮-醋酸乙烯酯共聚物而言，其溶解Td的能力最强。分散在聚丙烯酸树脂IR中的Td的结晶倾向可以通过固体分散体的低玻璃化转变温度（113°C）以及Td与聚合物之间最大的汉森溶解度参数差异（6.8MPa(0.5)）来解释，尽管这种关系对于聚乙烯吡咯烷酮中的部分结晶分散体并不成立。同样，使用红外光谱研究的氢键强度与固体分散体的物理稳定性或水溶液中的过饱和水平之间没有相关性。
