Role of the Strength of Drug-Polymer Interactions on the Molecular Mobility and Crystallization Inhibition in Ketoconazole Solid Dispersions

Pinal Mistry, Sarat Mohapatra, Tata Gopinath, Frederick G. Vogt, Raj Suryanarayanan

Research output: Contribution to journalArticlepeer-review

109 Scopus citations

Abstract

The effects of specific drug-polymer interactions (ionic or hydrogen-bonding) on the molecular mobility of model amorphous solid dispersions (ASDs) were investigated. ASDs of ketoconazole (KTZ), a weakly basic drug, with each of poly(acrylic acid) (PAA), poly(2-hydroxyethyl methacrylate) (PHEMA), and polyvinylpyrrolidone (PVP) were prepared. Drug-polymer interactions in the ASDs were evaluated by infrared and solid-state NMR, the molecular mobility quantified by dielectric spectroscopy, and crystallization onset monitored by differential scanning calorimetry (DSC) and variable temperature X-ray diffractometry (VTXRD). KTZ likely exhibited ionic interactions with PAA, hydrogen-bonding with PHEMA, and weaker dipole-dipole interactions with PVP. On the basis of dielectric spectroscopy, the α-relaxation times of the ASDs followed the order: PAA > PHEMA > PVP. In addition, the presence of ionic interactions also translated to a dramatic and disproportionate decrease in mobility as a function of polymer concentration. On the basis of both DSC and VTXRD, an increase in strength of interaction translated to higher crystallization onset temperature and a decrease in extent of crystallization. Stronger drug-polymer interactions, by reducing the molecular mobility, can potentially delay the crystallization onset temperature as well as crystallization extent.

Original languageEnglish (US)
Pages (from-to)3339-3350
Number of pages12
JournalMolecular pharmaceutics
Volume12
Issue number9
DOIs
StatePublished - Sep 8 2015

Keywords

  • amorphous solid dispersions
  • crystallization
  • dielectric spectroscopy
  • hydrogen bonding
  • infrared spectroscopy
  • ionic interaction
  • ketoconazole
  • molecular mobility
  • solid-state nuclear magnetic resonance

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