title: Lipid-Based Formulations Can Enable the Model Poorly Water-Soluble Weakly Basic Drug Cinnarizine To Precipitate in an Amorphous-Salt Form During In Vitro Digestion.
abstract: The tendency for poorly water-soluble weakly basic drugs to precipitate in a noncrystalline form during the in vitro digestion of lipid-based formulations (LBFs) was linked to an ionic interaction between drug and fatty acid molecules produced upon lipid digestion. Cinnarizine was chosen as a model weakly basic drug and was dissolved in a medium-chain (MC) LBF, which was subject to in vitro lipolysis experiments at various pH levels above and below the reported pKavalue of cinnarizine (7.47). The solid-state form of the precipitated drug was analyzed using X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and crossed polarized light microscopy (CPLM). In addition, the phase distribution of cinnarizine upon lipolysis was analyzed using high-performance liquid chromatography (HPLC). Cinnarizine precipitated in a noncrystalline form during lipolysis experiments at pH 6.5, pH 5.5, and pH 4.0 but precipitated in a crystalline form at pH 8.0 according to XRD measurements on the pellets. Differences were also observed in the FTIR spectra of the pellet phases at pH 8.0 and pH 6.5, with the absorption bands in the C-N stretch region of the IR spectra supporting a shift from the starting free base crystalline material to the hydrochloride salt, thus supporting the case that ionic interactions between weak bases and fatty acid molecules during digestion are responsible for producing amorphous-salts upon precipitation. The conclusion has wide implications for understanding past in vitro and in vivo data for lipid-based formulations of basic drugs, as well as future formulation design and optimization.
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences , Monash University (Parkville Campus), 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Jamal
authors.initials: J
authors.lastname: Khan
authors.affiliation: Department of Pharmaceutical Sciences, University of Copenhagen , Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rades
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences , Monash University (Parkville Campus), 381 Royal Parade, Parkville, Victoria 3052, Australia.|ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Ben J
authors.initials: BJ
authors.lastname: Boyd
mesh_terms: D002851:Chromatography, High Pressure Liquid; D002936:Cinnarizine / Q000737:chemistry*; D004339:Drug Compounding / Q000379:methods*; D006863:Hydrogen-Ion Concentration; D008859:Microscopy, Polarization; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D014867:Water / Q000737:chemistry; D014961:X-Ray Diffraction
chemical_list: D014867:Water; D002936:Cinnarizine
keywords: X-ray powder diffraction; lipids; poorly water-soluble drugs; precipitation; self-emulsifying; solid state