Kaminska E, Tarnacka M, Kolodziejczyk K, Dulski M, Zakowiecki D, Hawelek L, Adrjanowicz K, Zych M, Garbacz G, Kaminski K
Eur J Pharm Biopharm. 2014 Nov;88(3):1094-104. doi: 10.1016/j.ejpb.2014.10.002.
Different experimental and theoretical techniques were applied to investigate basic physical properties of very stable and homogeneous solid dispersions formed by itraconazole and octaacetylmaltose. Differential scanning calorimetry as well as semi-empirical calculations have indicated that liquid crystalline ordering in itraconazole was completely suppressed in the binary mixtures. Molecular dynamics studies with the use of broadband dielectric spectroscopy have shown that the width of the structural relaxation process becomes smaller and fragility drops in solid dispersions with respect to the pure itraconazole. Moreover, the dynamics of secondary relaxation processes was affected by acetylated maltose. As demonstrated, β- and γ-secondary modes shift to higher and lower frequencies, respectively. On the other hand, aging experiments revealed that isostructural relaxation times in the glassy state become systematically longer with the addition of modified carbohydrate. This is a very important finding in the context of the current discussion on the factors affecting physical stability of easily crystallizing APIs. It seems that beside intermolecular interactions and local reorientation, the global mobility might control the crystallization of amorphous solid dispersions. Finally, we have demonstrated that itraconazole in binary mixtures dissolves faster and to greater extent with respect to the crystalline and amorphous form of this API.
采用不同的实验和理论技术来研究由伊曲康唑和八乙酰麦芽糖形成的非常稳定且均匀的固体分散体的基本物理性质。差示扫描量热法以及半经验计算表明，在二元混合物中伊曲康唑的液晶有序性被完全抑制。使用宽带介电谱的分子动力学研究表明，相对于纯伊曲康唑，固体分散体中结构弛豫过程的宽度变小且脆性降低。此外，二级弛豫过程的动力学受乙酰化麦芽糖的影响。结果表明，β-和γ-二级模式分别向更高和更低频率移动。另一方面，老化实验表明，随着改性碳水化合物的加入，玻璃态下的同结构弛豫时间系统性变长。在当前关于影响易结晶活性药物成分物理稳定性因素的讨论背景下，这是一个非常重要的发现。似乎除了分子间相互作用和局部重排外，整体迁移率可能控制无定形固体分散体的结晶。最后，我们证明了二元混合物中的伊曲康唑相对于该活性药物成分的结晶形式和无定形形式溶解得更快且程度更大。
