Kalra Arjun, Tishmack Patrick, Lubach Joseph W, Munson Eric J, Taylor Lynne S, Byrn Stephen R, Li Tonglei
Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University , West Lafayette, Indiana 47907, United States.
SSCI , West Lafayette, Indiana 47906, United States.
Mol Pharm. 2017 Jun 5;14(6):2126-2137. doi: 10.1021/acs.molpharmaceut.7b00245. Epub 2017 May 17.
Despite numerous challenges in their theoretical description and practical implementation, amorphous drugs are of growing importance to the pharmaceutical industry. One such challenge is to gain molecular level understanding of the propensity of a molecule to form and remain as a glassy solid. In this study, a series of structurally similar diarylamine compounds was examined to elucidate the role of supramolecular aggregation on crystallization kinetics from supercooled liquid state. The structural similarity of the compounds makes it easier to isolate the molecular features that affect crystallization kinetics and glass forming ability of these compounds. To examine the role of hydrogen-bonded aggregation and motifs on crystallization kinetics, a combination of thermal and spectroscopic techniques was employed. Using variable temperature FTIR, Raman, and solid-state NMR spectroscopies, the presence of hydrogen bonding in the melt and glassy state was examined and correlated with observed phase transition behaviors. Spectroscopic results revealed that the formation of hydrogen-bonded aggregates involving carboxylic acid and pyridine nitrogen (acid-pyridine aggregates) between neighboring molecules in the melt state impedes crystallization, while the presence of carboxylic acid dimers (acid-acid dimers) in the melt favors crystallization. This study suggests that glass formation of small molecules is influenced by the type of intermolecular interactions present in the melt state and the kinetics associated with the molecules to assemble into a crystalline lattice. For the compounds that form acid-pyridine aggregates, the formation of energy degenerate chains, produced due to conformational flexibility of the molecules, presents a kinetic barrier to crystallization. The poor crystallization tendency of these aggregates stems from the highly directional hydrogen-bonding interactions needed to form the acid-pyridine chains. Conversely, for the compounds that form acid-acid dimers, the nondirectional van der Waals forces needed to construct a nucleus promote rapid assembly and crystallization.
尽管在非晶态药物的理论描述和实际应用中存在诸多挑战，但它们对制药行业的重要性与日俱增。其中一个挑战是要在分子水平上理解分子形成并保持为玻璃态固体的倾向。在本研究中，考察了一系列结构相似的二芳基胺化合物，以阐明超分子聚集体对过冷液态结晶动力学的作用。这些化合物的结构相似性使得更容易分离出影响其结晶动力学和玻璃形成能力的分子特征。为了研究氢键聚集和基序对结晶动力学的作用，采用了热分析和光谱技术相结合的方法。利用变温傅里叶变换红外光谱（FTIR）、拉曼光谱和固态核磁共振光谱，研究了熔体和玻璃态中氢键的存在情况，并将其与观察到的相变行为相关联。光谱结果表明，在熔体状态下，相邻分子之间形成涉及羧酸和吡啶氮的氢键聚集体（酸 - 吡啶聚集体）会阻碍结晶，而熔体中羧酸二聚体（酸 - 酸二聚体）的存在则有利于结晶。本研究表明，小分子的玻璃形成受熔体状态下存在的分子间相互作用类型以及分子组装成晶格相关动力学的影响。对于形成酸 - 吡啶聚集体的化合物，由于分子的构象灵活性产生的能量简并链的形成对结晶构成了动力学障碍。这些聚集体结晶倾向较差源于形成酸 - 吡啶链所需的高度定向氢键相互作用。相反，对于形成酸 - 酸二聚体的化合物，构建晶核所需的非定向范德华力促进了快速组装和结晶。
