Yoshioka Sumie, Aso Yukio
National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
J Pharm Sci. 2007 May;96(5):960-81. doi: 10.1002/jps.20926.
Recent studies have demonstrated that molecular mobility is an important factor affecting the chemical stability of amorphous pharmaceuticals, including small-molecular-weight drugs, peptides and proteins. However, quantitative correlations between molecular mobility and chemical stability have not yet been elucidated. The purpose of this article is to review literature describing the effect of molecular mobility on chemical stability during storage of amorphous pharmaceuticals, and to seek a better understanding of the relative significance of molecular mobility and other factors for chemical reactivity. We first consider the feature of chemical stability often observed for amorphous pharmaceuticals; changes in temperature dependence of chemical stability around matrix glass transition temperature (Tg), and greater stability associated with higher Tg. Secondly, we review papers which quantitatively studied the effects of the global mobility (often referred to as structural relaxation or -relaxation) of amorphous pharmaceuticals on chemical stability, and discuss correlations between chemical stability and global mobility using various equations that have thus far been proposed. Thirdly, the significance of local mobility of drug and excipient molecules in chemical reactivity is discussed in comparison with that of global mobility. Furthermore, we review literature reports which show no relationship between chemical stability and molecular mobility. The lack of apparent relationship is discussed in terms of the effects of the contribution of excipient molecules as reactants, the specific effects of water molecules, the heterogeneity of the matrix, and so on. The following summary has been obtained; the chemical stability of amorphous pharmaceuticals is affected by global mobility and/or local mobility, depending on the length scale of molecular mobility responsible for the chemical reactivity. In some cases, when activation energy for degradation processes is high and when other factors such as the specific effects of water and/or excipients contribute the degradation rate, stability seems to be largely independent of molecular mobility.
最近的研究表明，分子流动性是影响无定形药物化学稳定性的一个重要因素，这些无定形药物包括小分子药物、肽和蛋白质。然而，分子流动性与化学稳定性之间的定量相关性尚未阐明。本文的目的是综述描述分子流动性对无定形药物储存期间化学稳定性影响的文献，并更好地理解分子流动性和其他因素对化学反应性的相对重要性。我们首先考虑无定形药物通常观察到的化学稳定性特征；基质玻璃化转变温度（Tg）附近化学稳定性的温度依赖性变化，以及与较高Tg相关的更高稳定性。其次，我们综述了定量研究无定形药物整体流动性（通常称为结构弛豫或β弛豫）对化学稳定性影响的论文，并使用迄今提出的各种方程讨论化学稳定性与整体流动性之间的相关性。第三，与整体流动性相比，讨论了药物和辅料分子局部流动性在化学反应性中的重要性。此外，我们还综述了表明化学稳定性与分子流动性之间没有关系的文献报道。从辅料分子作为反应物的贡献、水分子的特定影响、基质的不均匀性等方面讨论了缺乏明显关系的情况。得到以下总结；无定形药物的化学稳定性受整体流动性和/或局部流动性的影响，这取决于负责化学反应性的分子流动性的长度尺度。在某些情况下，当降解过程的活化能较高，并且当水和/或辅料的特定影响等其他因素对降解速率有贡献时，稳定性似乎在很大程度上与分子流动性无关。
