Masuda Katsuhiko, Tabata Sachio, Sakata Yasuyuki, Hayase Tetsuo, Yonemochi Etsuo, Terada Katsuhide
Department of Pharmaceutics, Toho University School of Pharmaceutical Sciences, Funabashi, Chiba, Japan.
Pharm Res. 2005 May;22(5):797-805. doi: 10.1007/s11095-005-2597-4. Epub 2005 May 17.
The purpose of the current study was to evaluate the molecular mobility of amorphous indomethacin and salicin in the relaxed glassy state based on spin-lattice relaxation times (T(1c)) and to clarify the effects of molecular mobility on their physical stability.
Pulverized glassy amorphous indomethacin and salicin samples were completely relaxed, and the T(1c) values were investigated using solid-state (13)C-nuclear magnetic resonance (NMR) at temperatures below the glass transition temperature (T(g)). All NMR spectra were obtained using the T(1c) measurement method combined with variable-amplitude cross-polarization, the Torchia method, and total sideband suppression method.
The T(1c) value of amorphous indomethacin indicated that 73% of carbons were in a state of monodispersive relaxation, suggesting that the amorphous state was relatively homogeneous and restricted, particularly in backbone carbons. On the other hand, 92% of carbons of amorphous salicin exhibited both fast and slow biphasic relaxation. Individual structures of the salicin molecules behaved heterogeneously, and thus the entire molecule showed relatively fast local as well as slow mobility.
At temperatures below T(g), amorphous salicin had relatively greater molecular mobility than amorphous indomethacin. This difference in the molecular mobility of the two compounds is correlated with their crystallization behavior. Solid-state (13)C NMR provides valuable information on the physical stability of amorphous pharmaceuticals.
本研究的目的是基于自旋晶格弛豫时间（T(1c)）评估无定形吲哚美辛和水杨苷在松弛玻璃态下的分子流动性，并阐明分子流动性对其物理稳定性的影响。
将玻璃态无定形吲哚美辛和水杨苷样品粉碎并完全松弛，在低于玻璃化转变温度（T(g)）的温度下使用固态(13)C核磁共振（NMR）研究T(1c)值。所有NMR谱均采用结合可变幅度交叉极化、Torchia方法和全边带抑制方法的T(1c)测量方法获得。
无定形吲哚美辛的T(1c)值表明73%的碳原子处于单分散弛豫状态，这表明无定形状态相对均匀且受限，特别是在主链碳原子中。另一方面，无定形水杨苷92%的碳原子表现出快速和慢速双相弛豫。水杨苷分子的各个结构表现出异质性，因此整个分子表现出相对较快的局部流动性以及较慢的流动性。
在低于T(g)的温度下，无定形水杨苷的分子流动性比无定形吲哚美辛相对更大。这两种化合物分子流动性的差异与其结晶行为相关。固态(13)C NMR为无定形药物的物理稳定性提供了有价值的信息。
