Elucidating the Molecular Interactions Occurring during Drug Precipitation of Weak Bases from Lipid-Based Formulations: A Case Study with Cinnarizine and a Long Chain Self-Nanoemulsifying Drug Delivery System

The aim of this study was to investigate if molecular interactions between the weak base cinnarizine and lipolysis products were affecting the morphology of precipitated drug formed during in vitrolipolysis. In vitrolipolysis studies of a self-nanoemulsifying drug delivery system with or without cinnarizine were conducted. The digestion phases (aqueous phase and pellet phase) were separated by ultracentrifugation, and the pellet was isolated and lyophilized. The lyophilized pellets were examined by X-ray powder diffraction, 13C solid-state nuclear magnetic resonance (13C NMR), 1H liquid-state NMR (1H NMR) spectroscopy and differential scanning calorimetry (DSC). The 13C NMR data indicated that the carbonyl groups and aliphatic part of the lipids undergo structural changes when the pellet contains cinnarizine. The 1H NMR data suggests interactions occurring around the nitrogens on cinnarizine and the carboxylic group of fatty acids. DSC thermograms showed cinnarizine to be homogeneously incorporated into the lipids of the pellet, and no free amorphous cinnarizine was present. The three techniques 13C NMR, 1H NMR, and DSC complement each other and suggest interactions to occur between fatty acids and cinnarizine, which in turn favors amorphous precipitation.