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Effect of Polymer Hydrophobicity on the Stability of Amorphous Solid Dispersions and Supersaturated Solutions of a Hydrophobic Pharmaceutical.
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2019-01-15 , DOI: 10.1021/acs.molpharmaceut.8b00972 Derek S Frank 1 , Adam J Matzger 1
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2019-01-15 , DOI: 10.1021/acs.molpharmaceut.8b00972 Derek S Frank 1 , Adam J Matzger 1
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Amorphous solid dispersions of pharmaceuticals often show improved solubility over crystalline forms. However, the crystallization of amorphous solid dispersions during storage, or from elevated supersaturation once dissolved, compromise the solubility advantage of delivery in the amorphous phase. To combat this phenomenon, polymer additives are often included in solid dispersions to inhibit crystallization; however, the optimal properties for polymer to stabilize against crystallization are not fully understood, and furthermore, it is not known how inhibition of precipitation from solution is related to the propensity of a polymer to inhibit crystallization from the amorphous phase. Here, polymers of varied hydrophobicity are employed as crystallization inhibitors in supersaturated solutions and amorphous solid dispersions of the BCS Class II pharmaceutical ethenzamide to investigate the chemical features of polymer that lead to long-term stability for a hydrophobic pharmaceutical. A postpolymerization functionalization strategy was employed to alter the hydrophobicity of poly( N-hydroxyethyl acrylamide) without changing physical properties such as number-average chain length. It was found that supersaturation maintenance for ethenzamide is improved by increasing the hydrophobicity of dissolved polymer in aqueous solution. Furthermore, amorphous solid dispersions of ethenzamide containing a more hydrophobic polymer showed superior stability compared to those containing a less hydrophobic polymer. This trend of increasing polymer hydrophobicity leading to improved amorphous stability is interpreted by parsing the effects of water absorption in amorphous solid dispersions using intermolecular interaction strengths derived from global structural analysis. By comparing the structure-function relationships, which dictate stability in solution and amorphous solid dispersions, the effect of hydrophobicity can be broadly understood for the design of polymers to impart stability throughout the application of amorphous solid dispersions.
中文翻译：
聚合物疏水性对疏水性药物非晶态固体分散体和过饱和溶液稳定性的影响。
药物的无定形固体分散体通常显示出优于结晶形式的溶解度。然而，在储存期间无定形固体分散体的结晶，或一旦溶解则由于升高的过饱和而结晶，损害了在无定形相中递送的溶解度优势。为了克服这种现象，固体分散体中通常会加入聚合物添加剂以抑制结晶。然而，对于聚合物稳定抗结晶的最佳性能尚未完全理解，此外，还不知道从溶液中沉淀的抑制与聚合物抑制从无定形相结晶的倾向如何相关。这里，具有不同疏水性的聚合物被用作BCS II类药物乙酰胺的过饱和溶液和无定形固体分散体中的结晶抑制剂，以研究可导致疏水性药物长期稳定性的聚合物化学特征。采用后聚合官能化策略来改变聚（N-羟乙基丙烯酰胺）的疏水性，而不改变物理性质，例如数均链长。已经发现，通过增加水溶液中溶解的聚合物的疏水性，可以改善对乙酰胺的过饱和维持率。此外，与含有较少疏水性聚合物的那些相比，含有较多疏水性聚合物的乙酰胺的无定形固体分散体显示出优异的稳定性。聚合物疏水性增加导致无定形稳定性提高的趋势可以通过使用整体结构分析得出的分子间相互作用强度解析无定形固体分散体中的吸水率来解释。通过比较决定溶液和无定形固体分散体稳定性的结构-功能关系，可以广泛地理解疏水性的影响，以设计聚合物，以在整个无定形固体分散体应用中赋予稳定性。
更新日期：2019-01-15
中文翻译：
聚合物疏水性对疏水性药物非晶态固体分散体和过饱和溶液稳定性的影响。
药物的无定形固体分散体通常显示出优于结晶形式的溶解度。然而，在储存期间无定形固体分散体的结晶，或一旦溶解则由于升高的过饱和而结晶，损害了在无定形相中递送的溶解度优势。为了克服这种现象，固体分散体中通常会加入聚合物添加剂以抑制结晶。然而，对于聚合物稳定抗结晶的最佳性能尚未完全理解，此外，还不知道从溶液中沉淀的抑制与聚合物抑制从无定形相结晶的倾向如何相关。这里，具有不同疏水性的聚合物被用作BCS II类药物乙酰胺的过饱和溶液和无定形固体分散体中的结晶抑制剂，以研究可导致疏水性药物长期稳定性的聚合物化学特征。采用后聚合官能化策略来改变聚（N-羟乙基丙烯酰胺）的疏水性，而不改变物理性质，例如数均链长。已经发现，通过增加水溶液中溶解的聚合物的疏水性，可以改善对乙酰胺的过饱和维持率。此外，与含有较少疏水性聚合物的那些相比，含有较多疏水性聚合物的乙酰胺的无定形固体分散体显示出优异的稳定性。聚合物疏水性增加导致无定形稳定性提高的趋势可以通过使用整体结构分析得出的分子间相互作用强度解析无定形固体分散体中的吸水率来解释。通过比较决定溶液和无定形固体分散体稳定性的结构-功能关系，可以广泛地理解疏水性的影响，以设计聚合物，以在整个无定形固体分散体应用中赋予稳定性。
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