Solid-state CP/MAS13C NMR studies on conformational polymorphism in sertraline hydrochloride, an antidepressant drug

The C(2) isotropic chemical shift values in solid-state CP/MAS C-13 NMR spectra of conformational polymorphs Form I (delta 28.5) and III (delta 22.9) of (1S,4S)-sertraline HCl (1) were correlated with a gamma-gauche effect resulting from the respective 162.6degrees antiperiplanar and 68.8degrees (+)-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 (delta 22.8) and DMSO-d(6) (delta 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 [73.8degreesC(2)-C(1)-N-CH3 torsion angle], 0.88 (168.7degrees), and 2.40 (-63.4degrees). A Boltzmann distribution of these conformations at 25degreesC is estimated to be respectively M 80.3,18.3, and 1.4. Copyright (C) 2002 John Wiley Sons, Ltd.