title: Mechanism of amorphous itraconazole stabilization in polymer solid dispersions: role of molecular mobility.
abstract: Physical instability of amorphous solid dispersions can be a major impediment to their widespread use. We characterized the molecular mobility in amorphous solid dispersions of itraconazole (ITZ) with each polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose acetate succinate (HPMCAS) with the goal of investigating the correlation between molecular mobility and physical stability. Dielectric spectra showed two mobility modes: α-relaxation at temperatures above the glass transition temperature (Tg) and β-relaxation in the sub-Tg range. HPMCAS substantially increased the α-relaxation time, with an attendant increase in crystallization onset time and a decrease in crystallization rate constant, demonstrating the correlation between α-relaxation and stability. The inhibitory effect on α-relaxation as well as stability was temperature dependent and diminished as the temperature was increased above Tg. PVP, on the other hand, affected neither the α-relaxation time nor the crystallization onset time, further establishing the link between α-relaxation and crystallization onset in solid dispersions. However, it inhibited the crystallization rate, an effect attributed to factors other than mobility. Interestingly, both of the polymers acted as plasticizers of β-relaxation, ruling out the latter's involvement in physical stability.
authors.affiliation: Department of Pharmaceutics, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Sunny P
authors.initials: SP
authors.lastname: Bhardwaj
authors.forename: Kapildev K
authors.initials: KK
authors.lastname: Arora
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Kwong
authors.forename: Allen
authors.initials: A
authors.lastname: Templeton
authors.forename: Sophie-Dorothee
authors.initials: SD
authors.lastname: Clas
authors.forename: Raj
authors.initials: R
authors.lastname: Suryanarayanan
mesh_terms: D003460:Crystallization; D004355:Drug Stability; D017964:Itraconazole / Q000737:chemistry*; D007700:Kinetics; D008747:Methylcellulose / Q000031:analogs & derivatives* / Q000737:chemistry; D011205:Povidone / Q000737:chemistry*; D017356:Synchrotrons; D013696:Temperature; D014961:X-Ray Diffraction
chemical_list: D017964:Itraconazole; C048331:hydroxypropylmethylcellulose acetate succinate; D008747:Methylcellulose; D011205:Povidone
keywords: HPMCAS; PVP; crystallization kinetics; crystallization onset; dielectric spectroscopy; itraconazole; molecular mobility; solid dispersion; synchrotron radiation