Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
J Pharm Sci. 2012 Sep;101(9):3413-24. doi: 10.1002/jps.23141. Epub 2012 Apr 4.
The mechanism of drug nanoparticle formation of phenytoin (DPH) and its derivatives monomethylphenytoin (MDPH) and dimethylphenytoin (DMDPH) was investigated. The drug, polyvinylpyrrolidone K17 (PVP), and sodium dodecyl sulfate were coground to obtain the ground mixture (GM). The DPH GM was amorphous; however, MDPH and DMDPH GMs contained drug crystals. Spectral changes in infrared and (13)C solid-state nuclear magnetic resonance were observed in the DPH GM, partially observed in the MDPH GM, and hardly observed in the DMDPH GM. Mean particle sizes of the DPH, MDPH, and DMDPH GM nanosuspension were almost the same; however, stability after storage differed in the order of DPH > MDPH > DMDPH. The intermolecular interaction between the drug and PVP reflected not only the crystallinity of the drug in the GM but also the stability of the GM suspension. The size and stiffness of drug nanoparticles were evaluated using atomic force microscopy. Crystallization of the amorphous GM and agglomeration of the primary nanocrystals were observed in the DPH GM suspension. In contrast, primary nanocrystals were observed in the DMDPH GM suspension. The size of the drug nanocrystals formed from the different molecular states of the drug in the GM reflects the agglomerated states in water and stability.
研究了苯妥英（DPH）及其衍生物单甲基苯妥英（MDPH）和二甲基苯妥英（DMDPH）的药物纳米颗粒形成机制。将药物、聚乙烯吡咯烷酮 K17（PVP）和十二烷基硫酸钠共研磨以获得研磨混合物（GM）。DPH GM 为无定形；然而，MDPH 和 DMDPH GM 含有药物晶体。在 DPH GM 中观察到红外和（13）C 固态核磁共振的光谱变化，在 MDPH GM 中部分观察到，在 DMDPH GM 中几乎观察不到。DPH、MDPH 和 DMDPH GM 纳米混悬剂的平均粒径几乎相同；然而，储存后的稳定性顺序为 DPH > MDPH > DMDPH。药物和 PVP 之间的分子间相互作用不仅反映了 GM 中药物的结晶度，还反映了 GM 悬浮液的稳定性。使用原子力显微镜评估药物纳米颗粒的大小和刚度。在 DPH GM 悬浮液中观察到无定形 GM 的结晶和初级纳米晶体的团聚。相比之下，在 DMDPH GM 悬浮液中观察到初级纳米晶体。从 GM 中药物的不同分子状态形成的药物纳米晶体的大小反映了在水中的团聚状态和稳定性。
