TY - JOUR
T1 - Mechanism of amorphous itraconazole stabilization in polymer solid dispersions
T2 - Role of molecular mobility
AU - Bhardwaj, Sunny P.
AU - Arora, Kapildev K.
AU - Kwong, Elizabeth
AU - Templeton, Allen
AU - Clas, Sophie Dorothee
AU - Suryanarayanan, Raj
N1 - Publisher Copyright:
© 2014 American Chemical Society.
PY - 2014/11/3
Y1 - 2014/11/3
N2 - 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 polyvinylpyrroli-done (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.
AB - 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 polyvinylpyrroli-done (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.
KW - Crystallization kinetics
KW - Crystallization onset
KW - Dielectric spectroscopy
KW - HPMCAS
KW - Itraconazole
KW - Molecular mobility
KW - PVP
KW - Solid dispersion
KW - Synchrotron radiation
UR - http://www.scopus.com/inward/record.url?scp=84923373929&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84923373929&partnerID=8YFLogxK
U2 - 10.1021/mp5004515
DO - 10.1021/mp5004515
M3 - Article
C2 - 25325389
AN - SCOPUS:84923373929
SN - 1543-8384
VL - 11
SP - 4228
EP - 4237
JO - Molecular pharmaceutics
JF - Molecular pharmaceutics
IS - 11
ER -