Correlating thermodynamic and kinetic parameters with amorphous stability.
Poor physical stability is one of the single most important factors limiting the widespread use of the amorphous state in pharmaceutics. The purpose of this study is to move away from the case study approach by investigating thermodynamic and kinetic parameters as potential predictors of physical stability of amorphous drugs for a larger sample set (12 drugs). The relaxation time, fragility index and configurational thermodynamic properties (enthalpy, entropy and Gibbs free energy) were calculated and correlated to the actual stability behaviour, obtained for 12 drugs. Below the glass transition temperature the relaxation time and fragility showed no correlation with the observed physical stability. All drugs were calculated to be 'fragile'. However, variation in the fragility index existed, with values spanning from 8.9 to 21.3, manifesting themselves as differences in the temperature dependencies of the relaxation times. A reasonable correlation between the thermodynamic parameters and the stability above T(g) was found, with the configurational entropy exhibiting the strongest correlation (r(2)=0.685). However, it could also be shown that below T(g) no clear relationship between the various factors determined and physical stability exists, indicating that stability predictions on the basis of relaxation time alone may be inadequate.
Graeser
Kirsten A
KA
School of Pharmacy, University of Otago, P.O. Box 56, Dunedin, New Zealand.
Patterson
James E
JE
Zeitler
J Axel
JA
Gordon
Keith C
KC
Rades
Thomas
T
D000465:Algorithms; D002152:Calorimetry, Differential Scanning; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D007700:Kinetics; D008968:Molecular Conformation; D004364:Pharmaceutical Preparations / Q000032:analysis; D013056:Spectrophotometry, Ultraviolet; D013816:Thermodynamics; D014961:X-Ray Diffraction
D004364:Pharmaceutical Preparations