The Otto H. York Department of Chemical, Biological and Pharmaceutical Engineering, New Jersey Institute of Technology, University Heights, Newark, NJ 07102, USA.
Drug Dev Ind Pharm. 2013 Jan;39(1):102-8. doi: 10.3109/03639045.2012.659188. Epub 2012 Feb 23.
Solid dispersion technologies such as hot-melt extrusion and spray drying are often used to enhance the solubility of poorly soluble drugs. The biggest challenge associated with solid dispersion systems is that amorphous drugs may phase-separate from the polymeric matrix and recrystallize during storage. A more fundamental understanding of drug-polymer mixtures is needed for the industry to embrace the solid dispersion technologies. In this study, a theoretical model based on Flory-Huggins lattice theory was utilized to predict the solubility of a model drug acetaminophen (APAP) in a semi-crystalline polymer poly(ethylene oxide) (PEO) at 300 K. The interaction parameter χ was calculated to be -1.65 from the depression of drug's melting temperature determined from rheological and differential scanning calorimetry analysis. The equilibrium solubility in amorphous PEO was estimated to be 11.7% at 300 K. Assuming no APAP molecules dissolve in the crystalline part of PEO, the adjusted theoretical solubility is around 2.3% considering PEO being 80% crystalline. The solubility of APAP in PEG 400 was calculated to be 14.6% by using the same χ value, close to the experimental measurement 17.1%. The drug's solubility could be altered noticeably by the change of both χ and polymer molecular weight. The study also suggests that the depression of drug's melting point is a good indicator for preliminary polymer screening. The polymer that reduces the melting point the most is likely to be most miscible with the drug.
固体分散体技术，如热熔挤出和喷雾干燥，通常用于提高难溶性药物的溶解度。与固体分散体系统相关的最大挑战是，无定形药物可能会从聚合物基质中相分离并在储存过程中重新结晶。为了使行业接受固体分散技术，需要对药物-聚合物混合物有更深入的了解。在这项研究中，利用基于 Flory-Huggins 晶格理论的理论模型来预测模型药物对乙酰氨基酚（APAP）在半结晶聚合物聚环氧乙烷（PEO）中的溶解度，在 300 K 下。通过流变学和差示扫描量热法分析测定药物熔点降低，计算出相互作用参数 χ 为-1.65。在 300 K 时，无定形 PEO 中的平衡溶解度估计为 11.7%。假设没有 APAP 分子溶解在 PEO 的结晶部分，考虑到 PEO 结晶度为 80%，调整后的理论溶解度约为 2.3%。使用相同的 χ 值计算出 APAP 在聚乙二醇 400 中的溶解度为 14.6%，接近实验测量值 17.1%。药物的溶解度可以通过 χ 和聚合物分子量的变化而显著改变。该研究还表明，药物熔点的降低是聚合物初步筛选的良好指标。降低熔点最多的聚合物很可能与药物的混溶性最好。
