Supramolecular assemblies of citalopram and escitalopram in β-cyclodextrin dimeric cavity: Crystallographic and theoretical insights

Cyclodextrin (CD) encapsulation improves physicochemical and pharmacological properties of selective serotonin reuptake inhibitors (SSRIs), which are efficacious in treating depression, a global mental health problem. Here, we scrutinize β-CD inclusion complexes with racemate citalopram (rac-CTP; 1) and escitalopram ((S)-CTP; 2) by combined single-crystal X-ray diffraction and DFT full-geometry optimization. X-ray analysis unveiled that the 2:2 inclusion complexes of 1 and 2 with similar inclusion modes and topologies are stabilized by various intermolecular interactions of host–guest CH···π, host–host OH···O H-bonds, and guest–guest F···F in the tail-to-tail dimeric asymmetric unit. In the crystals, these dimers are stacked on top of each other, yielding similar channel structures of distinct crystal symmetries, triclinic, P1 (1) and monoclinic, P21 (2), which are further maintained by guest–guest π···π and CN···π interactions. The thermodynamic stabilities evaluated by DFT calculation indicate the vital role of weak intermolecular interactions in the formation and stabilization of the β-CD monomeric and dimeric inclusion complexes. This study provides crystallographic and theoretical evidence for the improved stability and the masked bitterness of CTP through β-CD encapsulation as patented previously and suggests the pharmaceutical implications in the drug delivery and enantioseparation.