Combining X-ray and NMR crystallography to explore the structural disorder in racemic propranolol hydrochloride†

Propranolol is a popular active pharmaceutical ingredient (API), a competitive non-cardioselective sympatholytic beta blocker, listed in the WHO Model List of Essential Medicines. Although, since its invention in 1962, multiple salts and cocrystals of propranolol have been obtained, in most of the commercially available drugs it exists in a form of racemic hydrochloride. Inconsistency exists in the previously deposited crystal structures of this salt, with some of them indicating structural disorder. Therefore, in this work the single crystal X-ray diffraction, solid state NMR and CASTEP periodic DFT calculations were combined to explain this phenomenon and characterize the crystal structure of this API. The obtained results clearly indicate the presence of static disorder in the crystal structure, pointing the most favorable arrangements. Besides, the comparison with the results obtained for the structures of pure enantiomers explained why the studied API forms racemic systems instead of complete chiral discrimination in the solid state.