Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/111201
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Type: Journal article
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
Author: Khan, J.
Rades, T.
Boyd, B.
Citation: Molecular Pharmaceutics, 2016; 13(11):3783-3793
Publisher: American Chemical Society
Issue Date: 2016
ISSN: 1543-8384
1543-8392
Statement of
Responsibility: 
Jamal Khan, Thomas Rades and Ben J. Boyd
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 pKa value 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.
Keywords: Water
Cinnarizine
Microscopy, Polarization
Chromatography, High Pressure Liquid
X-Ray Diffraction
Spectroscopy, Fourier Transform Infrared
Drug Compounding
Hydrogen-Ion Concentration
Solubility
Rights: © 2016 American Chemical Society
DOI: 10.1021/acs.molpharmaceut.6b00594
Grant ID: http://purl.org/au-research/grants/arc/DP120104032
ARC
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