Yang Ziyi, Nollenberger Kathrin, Albers Jessica, Qi Sheng
School of Pharmacy, University of East Anglia , Norwich, Norfolk NR4 7TJ, U.K.
Mol Pharm. 2014 Jul 7;11(7):2453-65. doi: 10.1021/mp500205c. Epub 2014 Jun 13.
The solubility of drugs in polymer matrixes has been recognized as one of the key factors governing the physical stability of solid dispersions. This study has explored the implications of drug solubility on the destabilization that occurs on milling, which is often used as an additional process for hot melt extruded (HME) solid dispersions. The theoretical drug solubility in the polymer was first predicted using various theoretical and experimental approaches. The destabilization effects of high-energy mechanical milling on the solid dispersions with drug loadings below and above the predicted solubility were then investigated using a range of thermal, microscopic, and spectroscopic techniques. Four model drug-polymer combinations were studied. The HME formulations with drug loading below the predicted solid solubility (undersaturated and true molecular dispersion) showed good stability against milling. In contrast, milling destabilized supersaturated HME dispersions via increasing molecular mobility and creating phase-separated, amorphous, drug-rich domains. However, these additional amorphous drug-rich domains created by milling show good stability under ambient conditions, though crystallization can be accelerated by additional heating. These results highlighted that the processing method used to prepare the solid dispersions may play a role in facilitating the stabilization of amorphous drug in supersaturated solid dispersions. The degree of supersaturation of the drug in the polymer showed significant impact on the destabilization behavior of milling on solid dispersions. An improved understanding of the destabilization behavior of solid dispersions upon milling can provide new insights into the processing related apparent solubility of drugs in polymers.
药物在聚合物基质中的溶解度已被认为是决定固体分散体物理稳定性的关键因素之一。本研究探讨了药物溶解度对研磨过程中发生的失稳现象的影响，研磨通常用作热熔挤出（HME）固体分散体的附加工艺。首先使用各种理论和实验方法预测了聚合物中药物的理论溶解度。然后使用一系列热学、显微镜和光谱技术研究了高能机械研磨对药物负载量低于和高于预测溶解度的固体分散体的失稳作用。研究了四种模型药物 - 聚合物组合。药物负载量低于预测固体溶解度（不饱和和真正的分子分散体）的HME制剂对研磨表现出良好的稳定性。相比之下，研磨通过增加分子流动性和形成相分离的、无定形的、富含药物的区域使过饱和HME分散体失稳。然而，通过研磨产生的这些额外的富含药物的无定形区域在环境条件下表现出良好的稳定性，尽管额外加热可以加速结晶。这些结果突出表明，用于制备固体分散体的加工方法可能在促进过饱和固体分散体中无定形药物的稳定化方面发挥作用。聚合物中药物的过饱和度对研磨对固体分散体的失稳行为有显著影响。对研磨时固体分散体失稳行为的更好理解可以为药物在聚合物中与加工相关的表观溶解度提供新的见解。
