Fluvoxamine: First comprehensive insights into its molecular characteristics and inclusion complexation with...

Area of Science:

• Pharmaceutical Chemistry
• Supramolecular Chemistry
• Structural Biology

Background:

• Selective serotonin reuptuptake inhibitors (SSRIs) like fluvoxamine (FXM) are crucial for treating depression and have shown potential for COVID-19 treatment.
• Cyclodextrin (CD) encapsulation is known to enhance the properties of SSRIs, but the molecular mechanisms remain poorly understood.
• Understanding these host-guest interactions is key to optimizing drug delivery and efficacy.

Purpose of the Study:

• To elucidate the molecular interactions between fluvoxamine (FXM) and β-cyclodextrin (β-CD) using crystallographic and computational methods.
• To provide detailed structural insights into the complexation of FXM with β-CD.
• To investigate the role of halogen interactions and drug conformation in the complexation process.

Main Methods:

• Single-crystal X-ray diffraction to determine the crystal structures of uncomplexed FXM and its β-CD complex.
• Density Functional Theory (DFT) calculations to analyze the stability and interactions within the complexes.
• Conformational analysis of FXM to understand its structural adaptability.

Main Results:

• The first crystallographic evidence of uncomplexed fluvoxamine maleate (FXM-H+·maleate-) was obtained.
• A tail-to-tail β-CD dimer was found to encapsulate FXM, stabilized by hydrogen bonds and halogen interactions (F⋯F, CF⋯π).
• DFT calculations confirmed the energetic stability of β-CD-FXM complexes and FXM isomers, explaining improved drug palatability.

Conclusions:

• The study provides unprecedented molecular insights into FXM-β-CD complexation, highlighting the significance of halogen interactions.
• The observed host-guest recognition pattern is crucial for β-CD complexes with halogen-bearing SSRIs.
• Understanding these interactions can guide the development of improved drug formulations with enhanced physicochemical properties and reduced side effects.