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

Abstract

Abstract The C(2) isotropic chemical shift values in solid‐state CP/MAS 13 C NMR spectra of conformational polymorphs Form I (δ 28.5) and III (δ 22.9) of (1 S ,4 S )‐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 C H 3 torsion angles as measured by X‐ray crystallography. The similarity of the solution‐state C(2) chemical shifts in CD 2 Cl 2 (δ 22.8) and DMSO‐ d 6 (δ 23.4) with that for Form III (and other polymorphs having C(2) C(1) N C H 3 (+)‐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 C H 3 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.