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

Research output: Contribution to journalJournal articlepeer-review

Standard

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. / Khan, Jamal; Rades, Thomas; Boyd, Ben J.

In: Molecular Pharmaceutics, Vol. 13, No. 11, 2016, p. 3783-3793.

Research output: Contribution to journalJournal articlepeer-review

Harvard

Khan, J, Rades, T & Boyd, BJ 2016, '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', Molecular Pharmaceutics, vol. 13, no. 11, pp. 3783-3793. https://doi.org/10.1021/acs.molpharmaceut.6b00594

APA

Khan, J., Rades, T., & Boyd, B. J. (2016). 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. Molecular Pharmaceutics, 13(11), 3783-3793. https://doi.org/10.1021/acs.molpharmaceut.6b00594

Vancouver

Khan J, Rades T, Boyd BJ. 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. Molecular Pharmaceutics. 2016;13(11):3783-3793. https://doi.org/10.1021/acs.molpharmaceut.6b00594

Author

Khan, Jamal ; Rades, Thomas ; Boyd, Ben J. / 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. In: Molecular Pharmaceutics. 2016 ; Vol. 13, No. 11. pp. 3783-3793.

Bibtex

@article{9a099968b0ec4112aeef77f5d65de41e,
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 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 = "lipids, poorly water-soluble drugs, precipitation, self-emulsifying, solid state, X-ray powder diffraction",
author = "Jamal Khan and Thomas Rades and Boyd, {Ben J}",
year = "2016",
doi = "10.1021/acs.molpharmaceut.6b00594",
language = "English",
volume = "13",
pages = "3783--3793",
journal = "Molecular Pharmaceutics",
issn = "1543-8384",
publisher = "American Chemical Society",
number = "11",

}

RIS

TY - JOUR

T1 - 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

AU - Khan, Jamal

AU - Rades, Thomas

AU - Boyd, Ben J

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

KW - lipids

KW - poorly water-soluble drugs

KW - precipitation

KW - self-emulsifying

KW - solid state

KW - X-ray powder diffraction

U2 - 10.1021/acs.molpharmaceut.6b00594

DO - 10.1021/acs.molpharmaceut.6b00594

M3 - Journal article

C2 - 27631273

AN - SCOPUS:84994494467

VL - 13

SP - 3783

EP - 3793

JO - Molecular Pharmaceutics

JF - Molecular Pharmaceutics

SN - 1543-8384

IS - 11

ER -

ID: 179166869