奥美沙坦与苯甲酸共晶的太赫兹光谱与密度泛函理论分析

doi:10.7503/cjcu20150351

摘要/Abstract

摘要：

利用太赫兹时域光谱技术(THz-TDS)与密度泛函理论(DFT)确定奥美沙坦与苯甲酸共晶的分子结构. THz-TDS实验结果显示, 奥美沙坦在0.53, 0.98和1.09 THz处存在吸收峰, 苯甲酸在0.65, 0.89和1.10 THz处存在吸收峰, 而奥美沙坦与苯甲酸共晶则在0.64和1.33 THz处存在吸收峰, 表明共晶体物相结构不同于原料物质. 根据奥美沙坦分子的结构特点, 采用DFT方法对奥美沙坦及奥美沙坦与苯甲酸共晶的3种可能共晶体结构进行模拟. 奥美沙坦模拟结果显示其理论光谱在0.76, 1.05和1.27 THz处存在吸收峰, 与实验相吻合; 而对奥美沙坦与苯甲酸所形成的共晶体, 模拟结果显示共晶理论晶型Ⅰ与共晶理论晶型Ⅱ及Ⅲ相比更吻合实验结果, 由此判断奥美沙坦与苯甲酸共晶结构应为共晶理论晶型Ⅰ. 在此共晶体中苯甲酸中羧酸的羰基与奥美沙坦的氨基形成一个氢键, 而此羧酸的羟基与奥美沙坦的五元环上的氮原子形成第2个氢键. 结合理论模拟的结果对奥美沙坦、奥美沙坦与苯甲酸共晶的吸收峰进行振动模式归属.

关键词: 奥美沙坦, 苯甲酸, 共晶, 太赫兹时域光谱, 密度泛函理论

Abstract:

The structure of cocrystal between olmesartan and benzoic acid was deterimined via terahertz time-domain spectroscopy(THz-TDS) technique and density functional theory(DFT). Experimental results show that all of them have distinctive and different fingerprint spectra in the THz region. The absorption peaks of olmesartan were at 0.53, 0.98, 1.09 THz and the absorption peaks of benzoic acid were at 0.65, 0.89, 1.10 THz. Characteristic bands observing in the terahertz spectra of cocrystal were at 0.64 and 1.33 THz, which were greatly different from corresponding raw starting materials. According to the structural characteristic of olmesartan molecule, density functional theory(DFT) program was used to simulate molecular structures and corresponding frequencies of olmesartan and three possible cocrystal forms considering the position of hydrogen bond formation between olmesartan and benzoic acid. The theoretical result showed that simulated olmesartan molecule had absorption peaks at 0.76, 1.05 and 1.27 THz, which was agreement with the THz experimental result. In addition, the theoretical results of three possible simulated cocrystal structures showed that FormⅠof simulated cocrystal was much better agreement with the experimental result than others. Therefore, the structure of cocrystal was confirmed that the first hydrogen bond was formed between amino group of olmesartan and hydroxyl group of benzoic acid, while the second one was formed between nitrogen atom of five nitrogen ring in olmesartan and carbonyl group of benzoic acid. The characteristic absorption bands of cocrystal between olmesartan and benzoic acid were also assigned based on the simulation results of DFT calculation.

Key words: Olmesartan, Benzoic acid, Cocrystal, Terahertz time-domain spectroscopy(THz-TDS), Density functional theory

中图分类号:

O641
O657.3

TrendMD:

方虹霞, 张琪, 张慧丽, 秦丹, 洪治, 杜勇. 奥美沙坦与苯甲酸共晶的太赫兹光谱与密度泛函理论分析. 高等学校化学学报, 2015, 36(12): 2504.

FANG Hongxia, ZHANG Qi, ZHANG Huili, QIN Dan, HONG Zhi, DU Yong. Terahertz Spectroscopic and Density Functional Theoretical Analysis of Cocrystal Between Olmesartan and Benzoic Acid^†. Chem. J. Chinese Universities, 2015, 36(12): 2504.

图/表 10

Fig.1 Molecular structure of olmesartan

Fig.2 Three theoretical structures of cocrystal between olmesartan and benzoic acid (1) FormⅠ; (B) form Ⅱ; (C) form Ⅲ.

Fig.3 Comparison of experimental(a) and theoretical(b) THz absorption spectra of olmesartan

Table 1 Comparison and assignment of theoretical spectrum and experimental spectrum for olmesartan

Frequency/THz		Vibrational mode
Expt.		Theo.
0.53	0.76	R3, N16H of R1 bending out of plane
0.98	1.05	C42—C45—C48, O11H, C8—C39—C52 and R1 bending out of plane
1.09	1.27	C42—C45—C48 and C39—C8—C5—C9 scissoring

Fig.4 Vibrational modes of olmesartan at 0.53 THz(A), 0.98 THz(B) and 1.09 THz(C)

Fig.5 THz spectra of olmesartan, benzoic acid and their cocrystal a. Cocrystal; b. olmesartan; c. physical mixture; d. benzoic acid.

Fig.6 Comparison of experimental(a) and theoretical forms Ⅰ(b), Ⅱ(c), Ⅲ(d) THz absorption spectra of cocrystal between olmesartan and benzoic acid

Table 2 Change of bond length of cocrystal between olmesartan and benzoic acid

Chemical bond	Bond length/nm
Chemical bond	Olmesartan	Benzoic acid	Cocrystal
C71=O72	—	0.1215	0.1231
C71—O73	—	0.1358	0.1329
O73—H74	—	0.9714	0.9965
N16—H38	0.1010	—	0.1028
N15—N16	0.1350	—	0.1343

Table 3 Vibration modes assginment of cocrystal between olmesartan and benzoic acid

Absorption peak frequency/THz	Vibrational mode
0.69	Benzoic acid and R1 twisting; R1, R2, C6—C42—C45—C48, C5—C9OOH and C56—C39—C52 bending out of plane
1.03	—C71OOH and R1 bending out of plane; the phenyl ring of benzoic acid and R2 bending out of plane; C6—C42—C45—C48, C5—C9OOH and C56—C3—C52 scissoring
1.58	R3 bending out of plane

Fig.7 Vibrational modes of theoretical cocrystal form Ⅰ between olmesartan and benzoic acid at 0.69 THz(A), 1.03 THz(B) and 1.58 THz(C)

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