Department of Chemical Engineering and Biotechnology, University of Cambridge, Philippa Fawcett Drive, Cambridge CB3 0AS, U.K.
Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.
Mol Pharm. 2022 Jan 3;19(1):227-234. doi: 10.1021/acs.molpharmaceut.1c00727. Epub 2021 Dec 2.
Terahertz time-domain spectroscopy (THz-TDS) is applied to two polymorphs of acetylsalicylic acid (aspirin), and the experimental spectra are compared to lattice dynamical calculations using high accuracy density functional theory. The calculations confirm that forms I and II have very close energetic and thermodynamic properties and also that they show similar spectral features in the far-infrared region, reflecting the high degree of similarity in their crystal structures. Unique vibrational modes are identified for each polymorph which allow them to be distinguished using THz-TDS measurements. The observation of spectral features attributable to both polymorphic forms in a single sample, however, provides further evidence to support the hypothesis that crystalline aspirin typically comprises intergrown domains of forms I and II. Differences observed in the baseline of the measured THz-TDS spectra indicate a greater degree of structural disorder in the samples of form II. Calculated Gibbs free-energy curves show a turning point at 75 K, inferring that form II is expected to be more stable than form I above this temperature as a result of its greater vibrational entropy. The calculations do not account for any differences in configurational entropy that may arise from expected structural defects. Further computational work on these structures, such as ab initio molecular dynamics, would be very useful to further explore this perspective. Here, aspirin is a model system to show how the additional insight from the low-frequency vibrational information complements the structural data and allows for quantitative thermodynamic information of pharmaceutical polymorphs to be extracted. The methodology is directly applicable to other polymorphic systems.
太赫兹时域光谱（THz-TDS）被应用于两种乙酰水杨酸（阿司匹林）的多晶型物，实验光谱与使用高精度密度泛函理论的晶格动力学计算进行了比较。计算结果证实，I 型和 II 型在能量和热力学性质上非常接近，并且它们在远红外区域显示出相似的光谱特征，这反映了它们晶体结构的高度相似性。为每种多晶型物确定了独特的振动模式，这使得可以使用 THz-TDS 测量来区分它们。然而，在单个样品中观察到两种多晶型物的光谱特征，进一步证明了结晶阿司匹林通常包含 I 型和 II 型的共生域的假设。在测量的 THz-TDS 光谱的基线中观察到的差异表明 II 型样品的结构无序程度更大。计算的吉布斯自由能曲线在 75 K 处出现转折点，推断由于其更大的振动熵，II 型在高于此温度时比 I 型更稳定。该计算未考虑可能由于预期结构缺陷而产生的构型熵的任何差异。对这些结构（例如从头算分子动力学）进行进一步的计算工作将非常有助于进一步探讨这一观点。在这里，阿司匹林是一个模型系统，用于展示低频振动信息的额外洞察力如何补充结构数据，并允许提取药物多晶型物的定量热力学信息。该方法可直接应用于其他多晶型系统。
