Structure of racemic duloxetine hydro-chloride

Mohan M Bhadbhade; Jiabin Gao; Anne M Rich; Christopher E Marjo

doi:10.1107/S2056989023003353

Structure of racemic duloxetine hydro-chloride

Acta Crystallogr E Crystallogr Commun. 2023 Apr 21;79(Pt 5):488-493. doi: 10.1107/S2056989023003353. eCollection 2023 Apr 1.

Authors

Mohan M Bhadbhade¹, Jiabin Gao², Anne M Rich¹, Christopher E Marjo¹

Affiliations

¹ Mark Wainwright Analytical Centre, The University of New South Wales, UNSW, Sydney NSW 2052, Australia.
² School of Chemistry, The University of New South Wales, UNSW Sydney NSW 2052, Australia.

Abstract

Duloxetine hydro-chloride (trade name Cymbalta) is marketed as a single enanti-omer (S)-N-methyl-3-(naphthalen-1-yl-oxy)-3-(thio-phen-2-yl)propyl-am-in-ium chloride, C₁₈H₂₀NOS⁺·Cl^-, which is twice as effective as the (R)-enanti-omer in serotonin uptake. Here, we report the crystal structure of duloxetine hydro-chloride in its racemic form (space group Pna2₁), where it shows significant differences in the mol-ecular conformation and packing in its extended structure compared to the previously reported (S)-enanti-omer crystal structure. Mol-ecules of this type, comprising aromatic groups with a single side chain terminated in a protonated secondary amine, are commonly found in active anti-depressants. A Cambridge Structural Database survey of mol-ecules with these features reveals a strong correlation between side-chain conformation and the crystal packing: an extended side chain leads to mol-ecules packed into separated layers of hydro-phobic and ionic hydro-philic phases. By comparison, mol-ecules with bent side chains, such as racemic duloxetine hydro-chloride, lead to crystal-packing motifs where an ionic hydro-philic phase is encapsulated within a hydro-phobic shell.

Keywords: anti-depressant drug; crystal structure; duloxetine; molecular packing; racemate; side chain conformation.