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Acta Physico-Chimica Sinca  2016, Vol. 32 Issue (9): 2241-2254    DOI: 10.3866/PKU.WHXB201606132
ARTICLE     
Determination and Correlation of the Absolute Configurations of Chiral Nimodipine
Dong GUO1,Jia-Xi SONG2,Dan LI1,Jia-Mei CHEN2,Li-Rong LIN1,Tong-Bu LU2,*(),Hui ZHANG1,*()
1 Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, Fujian Province, P. R. China
2 School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, P. R. China
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Abstract  

The stereochemical structures and absolute configuration-pharmacological activity relationship of chiral l, 4-dihydropyridines (1, 4-DHPs) calcium channel drugs were summarized. Additionally, the polymorphic forms of nimodipine were investigated. The absolute configurations of a pair of chiral nimodipines as a conglomerate prepared by spontaneous resolution under chiral crystallization were confirmed via X-ray crystallographic analysis directly correlated with their solid-state and solution electronic circular dichroism (ECD) spectra. The solid-state and solution ECD spectra of chiral l, 4-DHPs were obtained for the first time. This comprehensive method can be used to determine the absolute configurations of small organic molecules. Furthermore, it can be extended to correlate the absolute configurations of other series of chiral l, 4-DHP derivatives in the future. We also presented some effective techniques to distinguish polymorphs of chiral active pharmaceutical ingredients (APIs), which differ from the non-chiral conventional methods, to allow qualitative identification of different chiral crystalline states of APIs in pharmaceutical preparations.



Key words1, 4-Dihydropyridine      Absolute configuration correlation      Nimodipine      Polymorphism      Active pharmaceutical ingredient      Spontaneous resolution      Electronic circular dichroism     
Received: 12 May 2016      Published: 13 June 2016
MSC2000:  O641  
Fund:  National Natural Science Foundation of China(21273175);National Natural Science Foundation of China(21331007);National Natural Science Foundation of China(21271150);Natural Science Foundation of Guangdong Province, China(S2012030006240)
Corresponding Authors: Tong-Bu LU,Hui ZHANG     E-mail: lutongbu@mail.sysu.edu.cn;huizhang@xmu.edu.cn
Cite this article:

Dong GUO,Jia-Xi SONG,Dan LI,Jia-Mei CHEN,Li-Rong LIN,Tong-Bu LU,Hui ZHANG. Determination and Correlation of the Absolute Configurations of Chiral Nimodipine. Acta Physico-Chimica Sinca, 2016, 32(9): 2241-2254.

URL:

http://www.whxb.pku.edu.cn/10.3866/PKU.WHXB201606132     OR     http://www.whxb.pku.edu.cn/Y2016/V32/I9/2241

Fig 1 Schematic illustration for the structures of 1, 4-dihydropyridine (1, 4-DHP) derivatives
Fig 2 Structures of 1, 4-dihydropyridine calcium antagonists
Fig 3 Four enantiomers of barnidipine with two chiral centers The first and second symbols in prefixes indicate the configurations of the 1, 4-dihydropyridine C4 position and the pyrrolidine C3 position, respectively.
Fig 4 Structure of S-(-)-amlodipine besylate
Fig 5 Two chiral l, 4-dihydropyridine derivatives applied to determining the absolute configuration of the S-(-)-amlodipine20
CompoundSolution UV λ/nmSolution ECD λ/nm (Δε/(L·mol-1·cm-1))Solid-state UV λ/nmSolid-state ECD λ/nm (+/-)a
NMD-Ⅰ355, 236375, 247
NMD-Ⅱ-1355, 236366 (+0.204), 326 (-0.216), 263 (+0.531), 236 (+0.942), 223 (-0.994)375, 247355(+), 300(-), 255(+), 241(-), 222(+)
NMD-Ⅱ-2355, 236366 (-0.124), 326 (+0.264), 263 (-0.424), 237 (-1.187), 217 (+0.836)375, 247355(-), 300(+), 255(-), 241(+), 222(-)
Table 1 UV and ECD spectra of nimodipine in solution and solid-state
Fig 6 Crystallization process of racemic nimodipine API: active pharmaceutical ingredient; THF: tetrahydrofuran
Fig 7 XRD patterns of NMD-I and NMD-Ⅱ
Fig 8 Solid-state ECD spectra of NMD-I and NMD-II
Fig 9 Structures of linezolid and finasteride
ItemValue
crystal formS-ⅡR-Ⅱrac-Ⅰ
empirical formulaC21H26N2O7C21H26N2O7C21H26N2O7
formula weight418.45418.45418.45
solventCH3OHCH3OHtetrahydrofuran
T/K99.98100.01100.01
crystal systemorthorhombicorthorhombicmonoclinic
space groupP212121P212121P21/c
wavelength/nm0.1541840.1541840.154184
unit cell dimensions
a/nm1.141850(10)1.141928(16)1.37559(3)
b/nm1.248660(10)1.248419(17)1.07255(2)
c/nm1.447210(10)1.446979(19)1.47743(4)
β/(°)9090104.30(2)
volume/nm30.00206341(3)0.00206282(5)0.00211224(9)
Z444
calculated density/(g·cm-3)1.3471.3471.3158
F(000)888888891.0
final R indices [I >2σ(I)]R=0.0319, wR2=0.0813R=0.0376, wR2=0.1029R=0.0469, wR2=0.1312
absolute structure parameter-0.08(14)0.00(16)
Table 2 Crystallographic and structural refinement parameters
Fig 10 X-ray crystal structures (space group P212121) of NMD-II-a (left, S-form) and NMD-II-b (right, R-form)
Fig 11 X-ray crystal structure of rac-I (space group P21/c)
Fig 12 Concentration gradient solid-state ECD spectra of the single crystal NMD-II-a (space group P212121, S-form) dispersed in KBr disks A crystal piece of the single crystal NMD-II-a was selected and ground into a powder. HT: voltage of photomultiplier; *mass fraction
Fig 13 Concentration gradient solid-state ECD spectra of NMD-II (left) and NMD-II-2 (right) in 200-315 nm region
Fig 14 Solid-state (left) and solution (right) ECD spectra of NMD-II-1 and NMD-II-2 in their optimum concentrations
Fig 15 Solution ECD spectra of chiral amlodipine in MeOH
Fig 16 Concentration gradient solid-state ECD spectra of chiral amlodipine with the KBr pellet method
Fig 17 Solution ECD spectrum of commercial levamlodipine Beslate in MeOH solution
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