Kirsten A. Graeser, James E. Patterson and Thomas Rades Pages 374 - 382 ( 9 )
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 τ = 6.9·104 s for quench-cooled and τ = 1.7·104 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.
Simvastatin, amorphous, physical stability, Kohlrausch-Williams-Watts, Adam-Gibbs, DSC
School of Pharmacy, University of Otago, Dunedin, New Zealand.