TY - JOUR

T1 - Applying thermodynamic and kinetic parameters to predict the physical stability of two differently prepared amorphous forms of simvastatin

AU - Graeser, Kirsten A

AU - Patterson, James E

AU - Rades, Thomas

PY - 2009

Y1 - 2009

N2 - Converting drugs from the crystalline to the amorphous state has gained increasing interest in the past decades as a potential method to overcome solubility issues of poorly water soluble drugs. A variety of techniques exist to convert the crystalline state of a drug to its amorphous form, including solution based, heat based and solid - solid conversion based methods. Inherent to the amorphous state, regardless of its preparation technique, is its physical instability and tendency to recrystallize. In this study, quench-cooled and cryo-milled simvastatin were compared with regards to their configurational thermodynamic parameters (entropy, enthalpy and Gibbs free energy) and mobility (relaxation times calculated using the Adam-Gibbs and Kohlrausch-Williams-Watts method). Stability studies showed quench-cooled simvastatin to be more stable than cryo-milled simvastatin. This was reflected in the calculated parameters although their absolute values did not agree with the stability behaviour. Relaxation time parameters of tau = 6.9 x 10(4) s for quench-cooled and tau = 1.7 x 10(4) s for cryo-milled simvastatin were calculated. The results from this study suggested that differences in the physical stability of amorphous forms prepared by different techniques are reflected in their mobility and thermodynamic parameters. Even though the predictive capabilities of these parameters for a set of different drugs may be limited, they can serve as a predictive tool for physical stability assessment if differently prepared amorphous forms of the same drug are investigated.

AB - Converting drugs from the crystalline to the amorphous state has gained increasing interest in the past decades as a potential method to overcome solubility issues of poorly water soluble drugs. A variety of techniques exist to convert the crystalline state of a drug to its amorphous form, including solution based, heat based and solid - solid conversion based methods. Inherent to the amorphous state, regardless of its preparation technique, is its physical instability and tendency to recrystallize. In this study, quench-cooled and cryo-milled simvastatin were compared with regards to their configurational thermodynamic parameters (entropy, enthalpy and Gibbs free energy) and mobility (relaxation times calculated using the Adam-Gibbs and Kohlrausch-Williams-Watts method). Stability studies showed quench-cooled simvastatin to be more stable than cryo-milled simvastatin. This was reflected in the calculated parameters although their absolute values did not agree with the stability behaviour. Relaxation time parameters of tau = 6.9 x 10(4) s for quench-cooled and tau = 1.7 x 10(4) s for cryo-milled simvastatin were calculated. The results from this study suggested that differences in the physical stability of amorphous forms prepared by different techniques are reflected in their mobility and thermodynamic parameters. Even though the predictive capabilities of these parameters for a set of different drugs may be limited, they can serve as a predictive tool for physical stability assessment if differently prepared amorphous forms of the same drug are investigated.

M3 - Journal article

C2 - 19534709

VL - 6

SP - 374

EP - 382

JO - Current Drug Delivery

JF - Current Drug Delivery

SN - 1567-2018

IS - 4

ER -