Influence of particle size and preparation methods on the physical and chemical stability of amorphous simvastatin.

This study investigated the factors influencing the stability of amorphous simvastatin. Quench-cooled amorphous simvastatin in two particle size ranges, 150-180 microm (QC-big) and < or =10 microm (QC-small), and cryo-milled amorphous simvastatin (CM) were prepared, and their physical and chemical stability were investigated. Physical stability (crystallization) of amorphous simvastatin stored at two conditions was monitored by X-ray powder diffractometry (XRPD) and diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS). Assessment of enthalpy relaxation of amorphous forms was conducted using DSC in order to link the physical and chemical stability with molecular mobility. Chemical stability was studied with high-performance liquid chromatography (HPLC). Results obtained from the current study revealed that the solubility of amorphous forms prepared by both methods was enhanced compared to the crystalline form. The rank of solubility was found to be QC-big=QC-small>CM>crystalline. For the physical stability, the highest crystallization rate was observed for CM, and the slowest rate was detected for QC-big, with an intermediate rate occurring for QC-small. QC exhibited lower molecular mobility and higher chemical degradation than CM. Therefore, the current study demonstrated that QC and CM have obvious differences in both physical and chemical properties. It was concluded that care should be taken when choosing preparation methods for making amorphous materials. Furthermore, particle size, a factor that has often been overlooked when dealing with amorphous materials, was shown to have an influence on physical stability of amorphous simvastatin.