Structure of racemic duloxetine hydrochloride

Abstract

Duloxetine hydrochloride (trade name Cymbalta) is marketed as a single enantiomer (S)-N-methyl-3-(naphthalen-1-yloxy)-3-(thiophen-2-yl)propylaminium chloride, C18H20NOS+·Cl−, which is twice as effective as the (R)-enantiomer in serotonin uptake. Here, we report the crystal structure of duloxetine hydrochloride in its racemic form (space group Pna21), where it shows significant differences in the molecular conformation and packing in its extended structure compared to the previously reported (S)-enantiomer crystal structure. Molecules of this type, comprising aromatic groups with a single side chain terminated in a protonated secondary amine, are commonly found in active antidepressants. A Cambridge Structural Database survey of molecules with these features reveals a strong correlation between side-chain conformation and the crystal packing: an extended side chain leads to molecules packed into separated layers of hydrophobic and ionic hydrophilic phases. By comparison, molecules with bent side chains, such as racemic duloxetine hydrochloride, lead to crystal-packing motifs where an ionic hydrophilic phase is encapsulated within a hydrophobic shell.