Mechanism of Amorphous Itraconazole Stabilization in Polymer Solid Dispersions: Role of Molecular Mobility

作者：Bhardwaj Sunny P; Arora Kapildev K; Kwong Elizabeth; Templeton Allen; Clas Sophie Dorothee; Suryanarayanan Raj^*

来源：Molecular Pharmaceutics, 2014, 11(11): 4228-4237.

DOI：10.1021/mp5004515

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: a-relaxation at temperatures above the glass transition temperature (T-g) and beta-relaxation in the sub-Tg range. HPMCAS substantially increased the a-relaxation time, with an attendant increase in crystallization onset time and a decrease in crystallization rate constant, demonstrating the correlation between a-relaxation and stability. The inhibitory effect on a-relaxation as well as stability was temperature dependent and diminished as the temperature was increased above T-g. PVP, on the other hand, affected neither the a-relaxation time nor the crystallization onset time, further establishing the link between a-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 beta-relaxation, ruling out the latter's involvement in physical stability.

• 出版日期2014-11