title: 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.
abstract: 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 vitro lipolysis. In vitro lipolysis 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, (13)C solid-state nuclear magnetic resonance ((13)C NMR), (1)H liquid-state NMR ((1)H NMR) spectroscopy and differential scanning calorimetry (DSC). The (13)C NMR data indicated that the carbonyl groups and aliphatic part of the lipids undergo structural changes when the pellet contains cinnarizine. The (1)H 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 (13)C NMR, (1)H NMR, and DSC complement each other and suggest interactions to occur between fatty acids and cinnarizine, which in turn favors amorphous precipitation.
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Sassene
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Mette D
authors.initials: MD
authors.lastname: Mosgaard
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Korbinian
authors.initials: K
authors.lastname: Löbmann
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Huiling
authors.initials: H
authors.lastname: Mu
authors.affiliation: Department of Food Science, Faculty of Science, University of Copenhagen , Rolighedsvej 26, 1958 Frederiksberg, Denmark.
authors.forename: Flemming H
authors.initials: FH
authors.lastname: Larsen
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rades
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, 2100 Copenhagen, Denmark.|Bioneer:Farma, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Anette
authors.initials: A
authors.lastname: Müllertz
mesh_terms: D002121:Calcium Channel Blockers / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D011232:Chemical Precipitation; D002626:Chemistry, Pharmaceutical; D002936:Cinnarizine / Q000737:chemistry*; D004337:Drug Carriers; D016503:Drug Delivery Systems; D008055:Lipids / Q000737:chemistry*; D008066:Lipolysis; D012995:Solubility; D013997:Time Factors
chemical_list: D002121:Calcium Channel Blockers; D004337:Drug Carriers; D008055:Lipids; D002936:Cinnarizine
keywords: amorphous; differential scanning calorimetry; interactions; lipid-based drug delivery systems; nuclear magnetic resonance spectroscopy; self-nanoemuslifying drug delivery systems; solid-state characterization; weak bases