Pharmaceutical Chemistry and Formulations , Ardelyx , 34175 Ardenwood Blvd , Fremont , California 94555 , United States.
Mol Pharm. 2019 Mar 4;16(3):943-951. doi: 10.1021/acs.molpharmaceut.8b00853. Epub 2019 Feb 14.
The conformational flexibility of organic molecules introduces more structural options for crystallization to occur but has potential complications, such as, reduced crystallization tendency and conformational polymorphism. Although a variety of energetically similar conformers could be anticipated, it is extremely difficult to predict the crystal conformation for conformationally flexible molecules. The present study investigates differences in thermodynamic parameters for the free base, c-FB, and an amorphous dihydrochloride salt, a-Di-HCl, of a conformationally flexible drug substance, tenapanor (RDX5791). A variety of complementary techniques such as, thermal analysis, powder X-ray diffraction (PXRD), and molecular modeling were used to assess the thermodynamic properties and the propensity of crystallization for a-FB and a-Di-HCl, tenapanor. Molecular modeling and total scattering measurements suggested that the a-Di-HCl salt exists in an open elongated state with local 1D stacking, which extends only to the first nearest neighbor, while the a-FB shows local stacking extending to the third nearest neighbor. The overall relaxation behavior, which typically is an indicator for physical stability, as measured by modulated temperature differential scanning calorimetry and PXRD suggested a nontypical dual relaxation process for the dihydrochloride salt form. The first relaxation was fast and occurred on warming from the quench conditions without any thermal annealing, while the second relaxation step followed a more traditional glass relaxation model, exhibiting an infinite relaxation time. Similar analysis for the a-FB suggested a comparatively shorter relaxation time (about 19 days) that results in its rapid crystallization. This observation is further validated with the extensive amount of physical stability data collected for the a-Di-HCl salt form of tenapanor under accelerated and stress stability conditions, as well as long-term storage for more than 3 years that show no change in its amorphous state.
有机分子的构象灵活性为结晶提供了更多的结构选择，但也存在潜在的复杂性，例如结晶倾向降低和构象多态性。尽管可以预期存在各种能量相似的构象，但对于构象灵活的分子，预测晶体构象极其困难。本研究考察了构象灵活的药物物质 tenapanor（RDX5791）的游离碱 c-FB 和无定形二盐酸盐 a-Di-HCl 的热力学参数差异。采用多种互补技术，如热分析、粉末 X 射线衍射（PXRD）和分子建模，评估了 a-FB 和 a-Di-HCl 的热力学性质和结晶倾向。分子建模和全散射测量表明，a-Di-HCl 盐以开放的伸长状态存在，具有局部一维堆积，仅延伸到第一近邻，而 a-FB 显示局部堆积延伸到第三近邻。整体弛豫行为通常是物理稳定性的指标，通过调制温度差示扫描量热法和 PXRD 测量，表明二盐酸盐形式存在非典型的双重弛豫过程。第一个弛豫过程很快，在从淬火条件升温时发生，无需任何热退火，而第二个弛豫步骤遵循更传统的玻璃弛豫模型，表现出无限的弛豫时间。对 a-FB 的类似分析表明，其弛豫时间相对较短（约 19 天），导致其快速结晶。这一观察结果进一步通过在加速和应力稳定性条件下以及在超过 3 年的长期储存下收集的大量 tenapanor 的 a-Di-HCl 盐形式的物理稳定性数据得到验证，在这些条件下，其无定形状态没有变化。
