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

The 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-d ₆ (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.