Investigation of the Dependence of the Flory-Huggins Interaction Parameter on Temperature and Composition in a Drug-Polymer System
Investigation of the Dependence of the Flory-Huggins Interaction Parameter on Temperature and Composition in a Drug-Polymer System
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DOI：
10.1021/acs.molpharmaceut.8b00797
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发表时间：
2018-11-01
影响因子：
4.9
通讯作者：
Walker, Gavin M.
中科院分区：
文献类型：
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作者：
Potter, Catherine B.;Davis, Mark T.;Walker, Gavin M.
Flory-Huggins （F-H）溶解度方程已被广泛用于描述小分子药物在聚合物载体中的溶解度，从而确定可用于制定稳定的非晶固体分散体的设计空间。F-H相互作用参数（chi）描述了药物-聚合物溶液的热力学性质，并解释了溶解度的任何焓和熵变化。许多研究发现，在一个有限的组成范围内，chi的变化与药物的熔化温度成反比。我们利用高灵敏度DSC技术，在接近估计溶解度曲线的温度下，对结晶伊曲康唑（ITZ）和Soluplus或邻苯二甲酸羟丙基甲基纤维素（HPMCP）的球磨混合物退火后，检测剩余的晶体活性药物成分（api），探索了这种关系。根据所采用的实验方法，药物-聚合物溶解度的测量可以限制在具有高比例药物的混合物中，但在本研究中，溶解度是通过实验确定的，API含量低至10 wt %。结果表明，所提出的线性关系并不适用于API含量较低的组合物，而是表明chi对所研究的系统既依赖于温度，也依赖于组合物。还确定了该技术在含有伊曲康唑和两种聚合物的三元体系中测量相互作用的可行性；ITZ- HPMCP表现出最有利的chi值，而ITZ- soluplus和ITZ- soluplus -HPMCP具有相似的相互作用参数。
The Flory-Huggins (F-H) solubility equation has been widely used to describe the solubility of a small molecule drug in a polymeric carrier and thus determine the design space available for formulating a stable amorphous solid dispersion. The F-H interaction parameter (chi) describes the thermodynamic properties of drug-polymer solutions and accounts for any enthalpic and entropic changes in solubility. Many studies have found that for a limited compositional range, chi varies proportionally to the inverse of the melting temperature of the drug. We explored this relationship using a highly sensitive DSC technique to detect remaining residual crystalline active pharmaceutical ingredients (APIs) following annealing of ball milled mixtures of crystalline itraconazole (ITZ) and either Soluplus or hydroxypropyl methylcellulose phthalate (HPMCP) at temperatures near the estimated solubility curve. Depending on the experimental approach taken, the measurement of drug-polymer solubility can be restricted to mixtures with a high proportion of drug, but in this study, solubility was experimentally determined for mixtures with API content as low as 10 wt %. Results suggest that the proposed linear relationship does not extend to compositions with smaller amounts of API, instead indicating that chi was both temperature- and composition-dependent for the systems studied. The feasibility of this technique to measure interactions in a ternary system containing itraconazole and both polymers was also determined; ITZ HPMCP exhibited the most favorable values of chi, while ITZ-Soluplus and ITZ-Soluplus-HPMCP demonstrated similar interaction parameters.