Solid‐state CP/MAS 13C NMR studies on conformational polymorphism in sertraline hydrochloride, an antidepressant drug

Abstract

AbstractThe C(2) isotropic chemical shift values in solid‐state CP/MAS 13C NMR spectra of conformational polymorphs Form I (δ 28.5) and III (δ 22.9) of (1S,4S)‐sertraline HCl (1) were correlated with a γ‐gauche effect resulting from the respective 162.6° antiperiplanar and 68.8° (+)‐synclinal C(2) C(1) N CH3 torsion angles as measured by X‐ray crystallography. The similarity of the solution‐state C(2) chemical shifts in CD2Cl2 (δ 22.8) and DMSO‐d6 (δ 23.4) with that for Form III (and other polymorphs having C(2) C(1) N CH3 (+)‐synclinal angles) strongly suggests that a conformational bias about the C(1) N bond exists for 1 in both solvents. This conclusion is supported by density functional theory B3LYP/6‐31G(d)‐calculated relative energies of C(1) N rotameric models: (kcal) 0.00 [73.8 °C(2) C(1) N CH3 torsion angle], 0.88 (168.7°), and 2.40 (−63.4°). A Boltzmann distribution of these conformations at 25 °C is estimated to be respectively (%) 80.3, 18.3, and 1.4. Copyright © 2002 John Wiley & Sons, Ltd.