TY - JOUR

T1 - Correlating thermodynamic and kinetic parameters with amorphous stability

AU - Graeser, Kirsten A

AU - Patterson, James E

AU - Zeitler, J Axel

AU - Gordon, Keith C

AU - Rades, Thomas

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

KW - Algorithms

KW - Calorimetry, Differential Scanning

KW - Chromatography, High Pressure Liquid

KW - Drug Stability

KW - Kinetics

KW - Molecular Conformation

KW - Pharmaceutical Preparations

KW - Spectrophotometry, Ultraviolet

KW - Thermodynamics

KW - X-Ray Diffraction

U2 - 10.1016/j.ejps.2009.04.005

DO - 10.1016/j.ejps.2009.04.005

M3 - Journal article

C2 - 19394421

VL - 37

SP - 492

EP - 498

JO - Norvegica Pharmaceutica Acta

JF - Norvegica Pharmaceutica Acta

SN - 0928-0987

IS - 3-4

ER -