利用太赫兹光谱和密度泛函理论研究烟酰胺-庚二酸共晶体的多晶型

烟酰胺, 又称为维生素PP，是辅酶Ⅰ和辅酶Ⅱ的组成部分，是许多脱氢酶的辅酶。庚二酸是一种广泛使用的共晶体前体。烟酰胺与庚二酸形成的药物共晶体具有两种不同的多晶型, 分别为晶型Ⅰ和晶型Ⅱ。不同的药物晶型常常具有不同的物理化学性质，这些差异可能会对药物的溶出速率、稳定性以及药效具有较大影响，因此在药物领域中寻找合适的技术手段鉴别药物的不同晶型非常重要。利用太赫兹时域光谱在室温下对烟酰胺-庚二酸的两种共晶体在0.2～2.2 THz范围内进行检测，发现两者的特征吸收峰具有明显的差异，晶型Ⅰ在1.51，1.73，1.94，2.01和2.17 THz有五个特征吸收峰，其中在1.94，2.01和2.17 THz处是三个吸收强度较大的峰，而晶型Ⅱ在1.66，1.74，1.88，2.02和2.16 THz有五个特征吸收峰，与晶型Ⅰ不同的是在2.02和2.16 THz处有两个强度较大的吸收峰。利用密度泛函理论对烟酰胺-庚二酸两种共晶体进行理论计算，计算结果表明实验峰与理论峰基本对应，对吸收峰指认归属表明特征吸收峰来源于分子骨架的振动与包含氢键的振动。研究结果表明太赫兹时域光谱技术对于区分药物共晶体的多晶型现象具有重要的应用。

Terahertz Spectroscopic and Density Functional Theory Investigation on the Polymorph of the Cocrystals of Nicotinamide and Pimelic Acid

Nicotinamide, also known as vitamin PP, is component of coenzyme Ⅰ and Ⅱ, and it turns into a coenzyme for most of dehydrogenases. Pimelic acid has also been utilized previously as a cocrystal former. A cocrystal of nicotinamide and pimelic acid exists in two different polymorphic form-Ⅰ and form-Ⅱ. It is important to find a suitable technical means in the pharmaceutical field since the polymorphs have different physio-chemical properties which influence their solubility, stability and also other performance characteristics. The absorption spectra of nicotinamide-pimelic acid cocrystal were measured using terahertz time-domain spectroscopy ranging from 0.2 to 2.2 THz at room temperature, and the absorption peaks have obvious difference. Form-Ⅰ and form-Ⅱ have five characteristic absorption peaks at 1.51, 1.73, 1.94, 2.01, 2.17 THz and 1.66, 1.74, 1.88, 2.02, 2.16 THz, respectively. Form-Ⅰ has three strong absorption peaks at 1.94, 2.01 and 2.17 THz, while form-Ⅱ has two strong absorption peaks at 2.02 and 2.16 THz. Density functional theory was used to simulate the polymorphs of the nicotinamide and pimelic cocrystal. The calculated characteristic peaks were in accord with those in the experiments. The results showed characteristic absorption bands come from skeletal and hydrogen bond vibrations. This research suggested that terahertz time-domain spectroscopy technique is important for applications in solid-state analytical tools to distinguish polymorphs of cocrystal in pharmaceutical fields.