Hasegawa Susumu, Furuyama Naho, Yada Shuichi, Hamaura Takeshi, Kusai Akira, Yonemochi Etsuo, Terada Katsuhide
Pharmaceutical Development Laboratories, Sankyo Co. Ltd., 1-12-1 Shinomiya, Hiratsuka, Kanagawa 254-0014, Japan.
Int J Pharm. 2007 May 4;336(1):82-9. doi: 10.1016/j.ijpharm.2006.11.041. Epub 2006 Nov 26.
This study examined the effect of physical properties of troglitazone drug substance on the molecular interaction with polyvinylpyrrolidone K30 (PVP) during preparation by a closed melting method. Milling was conducted using impact and jet mills to change the physical properties of troglitazone, such as particle size, specific surface area, surface free energy and acidic-basic parameters. Solid dispersions (SDs) prepared from milled troglitazone, irrespective of milling method, showed almost 100% dissolution when not less than 7.5% of water was added during heating. SDs prepared from unmilled troglitazone showed almost 100% dissolution when not less than 12.8% of water was added during heating. Physical mixture (PM) containing unmilled troglitazone must be heated above at least 50 degrees C higher than the glass transition temperature (T(g)) of PVP to obtain an SD showing 100% dissolution, while PMs containing milled troglitazone could be heated above only 20 degrees C higher than the T(g) of PVP to obtain an SD showing 100% dissolution. The melting points of troglitazone in PMs containing milled troglitazone, irrespective of milling method, were lower than those in PMs containing unmilled troglitazone. These results indicated that specific interaction could occur more easily during heating between milled troglitazone and PVP during preparation by a closed melting method. In addition, Fourier transform infrared study indicated that hydrogen bonding could occur between the N-H of troglitazone and the C=O of PVP.
本研究考察了在采用密闭熔融法制备过程中，曲格列酮原料药的物理性质对其与聚乙烯吡咯烷酮K30（PVP）分子间相互作用的影响。使用冲击式磨机和气流粉碎机进行研磨，以改变曲格列酮的物理性质，如粒径、比表面积、表面自由能和酸碱参数。无论采用何种研磨方法，由研磨后的曲格列酮制备的固体分散体（SDs）在加热过程中加入不少于7.5%的水时，几乎能100%溶解。由未研磨的曲格列酮制备的SDs在加热过程中加入不少于12.8%的水时，几乎能100%溶解。含有未研磨曲格列酮的物理混合物（PM）必须加热到比PVP的玻璃化转变温度（T(g)）至少高50摄氏度以上，才能得到100%溶解的SDs，而含有研磨后曲格列酮的PMs只需加热到比PVP的T(g)高20摄氏度以上，就能得到100%溶解的SDs。无论采用何种研磨方法，含有研磨后曲格列酮的PMs中曲格列酮的熔点均低于含有未研磨曲格列酮的PMs。这些结果表明，在采用密闭熔融法制备过程中，研磨后的曲格列酮与PVP在加热过程中更容易发生特定的相互作用。此外，傅里叶变换红外光谱研究表明，曲格列酮的N-H与PVP的C=O之间可能形成氢键。
