title: Physical stability of the amorphous anticholesterol agent (ezetimibe): the role of molecular mobility.
abstract: The purpose of this paper is to examine the role of molecular mobility in the recrystallization process from the amorphous state of the anticholesterol drug ezetimibe. Both the molecular dynamics and crystallization kinetics have been studied using various experimental techniques, such as broadband dielectric spectroscopy (BDS), differential scanning calorimetry (DSC), and X-ray diffraction (XRD). Our investigations have shown that ezetimibe easily recrystallizes from the disordered state, both below and above its glass transition temperature (Tg = 336 K). Moreover, we found that an only slightly elevated pressure (5 MPa) significantly accelerates the recrystallization process at T > Tg. We predict that the structural relaxation time of amorphous ezetimibe at 293 K (storage temperature) and ambient pressure is only 22 days. This result corresponds to the characteristic time, determined from XRD measurements, for amorphous ezetimibe to recrystallize during storage at Troom = 298 K. It leads to the conclusion that the molecular mobility reflected in structural relaxation of ezetimibe is mainly responsible for devitrification of this drug. Finally, we determined a relatively easy way to improve the physical stability of the drug by preparing a binary amorphous ezetimibe-Soluplus mixture. Ezetimibe in an amorphous mixture with 20 wt % Soluplus has a much better (over six times) solubility than the pure crystalline material.
authors.affiliation: Institute of Physics, University of Silesia , ul. Uniwersytecka 4, 40-007 Katowice, Poland.
authors.forename: J
authors.initials: J
authors.lastname: Knapik
authors.forename: Z
authors.initials: Z
authors.lastname: Wojnarowska
authors.forename: K
authors.initials: K
authors.lastname: Grzybowska
authors.forename: L
authors.initials: L
authors.lastname: Hawelek
authors.forename: W
authors.initials: W
authors.lastname: Sawicki
authors.forename: K
authors.initials: K
authors.lastname: Wlodarski
authors.forename: J
authors.initials: J
authors.lastname: Markowski
authors.forename: M
authors.initials: M
authors.lastname: Paluch
mesh_terms: D000924:Anticholesteremic Agents / Q000737:chemistry*; D001384:Azetidines / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D003460:Crystallization; D058266:Dielectric Spectroscopy; D004355:Drug Stability; D000069438:Ezetimibe; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D044366:Transition Temperature; D014961:X-Ray Diffraction
chemical_list: D000924:Anticholesteremic Agents; D001384:Azetidines; D000069438:Ezetimibe
keywords: Soluplus; amorphous drug; crystallization; ezetimibe; glass transition; molecular dynamics; physical stability; stability predicting