title: Role of the Strength of Drug-Polymer Interactions on the Molecular Mobility and Crystallization Inhibition in Ketoconazole Solid Dispersions.
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.
authors.forename: Pinal
authors.initials: P
authors.lastname: Mistry
authors.forename: Sarat
authors.initials: S
authors.lastname: Mohapatra
authors.forename: Tata
authors.initials: T
authors.lastname: Gopinath
authors.affiliation: Morgan, Lewis, and Bockius LLP, Philadelphia, Pennsylvania 19103, United States.
authors.forename: Frederick G
authors.initials: FG
authors.lastname: Vogt
authors.forename: Raj
authors.initials: R
authors.lastname: Suryanarayanan
mesh_terms: D000180:Acrylic Resins / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D003460:Crystallization; D004347:Drug Interactions; D004355:Drug Stability; D006860:Hydrogen Bonding; D007654:Ketoconazole / Q000737:chemistry*; D008689:Methacrylates / Q000737:chemistry*; D044367:Phase Transition; D011108:Polymers / Q000737:chemistry*; D011205:Povidone / Q000737:chemistry*; D017550:Spectroscopy, Fourier Transform Infrared; D014961:X-Ray Diffraction
chemical_list: D000180:Acrylic Resins; D008689:Methacrylates; D011108:Polymers; C006903:carbopol 940; C005044:hydroxyethyl methacrylate; D011205:Povidone; D007654:Ketoconazole
keywords: amorphous solid dispersions; crystallization; dielectric spectroscopy; hydrogen bonding; infrared spectroscopy; ionic interaction; ketoconazole; molecular mobility; solid-state nuclear magnetic resonance