Yoshioka Sumie, Aso Yukio
National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
J Pharm Sci. 2005 Feb;94(2):275-87. doi: 10.1002/jps.20244.
The purpose of this study was to explore why changes in the molecular mobility associated with glass transition, the timescale of which is on the order of 100 s, can be detected by measuring the nuclear magnetic resonance relaxation times that reflect molecular motions on the order of 10 kHz and 1 MHz. The molecular motions in freeze-dried dextran 40k, dextran 1k, isomaltotriose (IMT), and alpha-glucose comprising a common unit but with different glass transition temperatures, were investigated by dielectric spectroscopy (DES) in the frequency range of 0.01 Hz to 100 kHz and in the temperature range of -20 degrees to 200 degrees C, in order to compare with the molecular motions reflected in nuclear magnetic resonance relaxation times. The alpha-relaxation process for freeze-dried alpha-glucose was visualized by DES, whereas those for freeze-dried dextran 40k, dextran 1k, and IMT were too slow to be visualized by DES. The latter freeze-dried cakes exhibited quasi-dc polarization because of proton-hopping-like motion rather than alpha-relaxation process. The correlation time (tau(c)) for the backbone carbon of dextran 40k and IMT, calculated from the measured value of spin-lattice relaxation time in the rotating frame, was found to be close to the relaxation time of proton-hopping-like motion determined by DES (tau(DES)) at temperatures around glass transition temperature. The timescales of molecular motions reflected in the tau(c) and tau(DES) were significantly smaller than that of motions leading to molecular rearrangement (molecular rearrangement motions), which correspond to alpha-relaxation. However, the shapes of temperature dependence for the tau(c) and tau(DES) were similar to that of the calorimetrically determined relaxation time of molecular rearrangement motions. Results suggest that the molecular motions reflected in the tau(c) and tau(DES) are linked to molecular rearrangement motions, such that enhancement of molecular rearrangement motions enhances the molecular motions reflected in the tau(c) and tau(DES). Thus, the tau(DES) and tau(c) can reflect changes in molecular mobility leading to unwanted changes in amorphous formulations, and are thought to be a useful measure for evaluating the stability of formulations.
本研究的目的是探究为何与玻璃化转变相关的分子迁移率变化（其时间尺度约为100秒）能够通过测量反映10千赫兹和1兆赫兹量级分子运动的核磁共振弛豫时间来检测。通过介电谱（DES）在0.01赫兹至100千赫兹的频率范围以及-20摄氏度至200摄氏度的温度范围内，研究了包含共同单元但具有不同玻璃化转变温度的冻干右旋糖酐40k、右旋糖酐1k、异麦芽三糖（IMT）和α-葡萄糖中的分子运动，以便与核磁共振弛豫时间所反映的分子运动进行比较。通过DES可视化了冻干α-葡萄糖的α-弛豫过程，而冻干右旋糖酐40k、右旋糖酐1k和IMT的α-弛豫过程则太慢，无法通过DES可视化。后几种冻干物由于类似质子跳跃的运动而非α-弛豫过程而表现出准直流极化。根据旋转坐标系中自旋晶格弛豫时间的测量值计算得出，右旋糖酐40k和IMT主链碳的相关时间（τc）在玻璃化转变温度附近的温度下，被发现与DES测定的类似质子跳跃运动的弛豫时间（τDES）接近。τc和τDES所反映的分子运动时间尺度明显小于导致分子重排的运动（分子重排运动）的时间尺度，后者对应于α-弛豫。然而，τc和τDES的温度依赖性形状与量热法测定的分子重排运动弛豫时间的形状相似。结果表明，τc和τDES所反映的分子运动与分子重排运动相关联，使得分子重排运动的增强会增强τc和τDES所反映的分子运动。因此，τDES和τc能够反映导致无定形制剂出现不良变化的分子迁移率变化，并且被认为是评估制剂稳定性的一种有用方法。
