An Investigation of the Impact of Precipitation Temperature and Filter Cake Thickness on the Physical Stability of Amorphous Solids: A Case Study

Abstract

The purpose of this study was to resolve the issue of physical instability in amorphous solid drugs, which can result in unwanted crystallization, affecting solubility and dissolution rates. The focus was on precipitating physically stable amorphous forms of the nilotinib free base, an anticancer drug, by monitoring preparation conditions such as precipitation temperature and filter cake thickness. A comprehensive set of characterization techniques, including powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and focused beam reflectance measurement (FBRM), were used. These were supplemented by advanced data analysis methods that incorporated pair distribution function (PDF), reduced crystallization temperature (Rc), and principal component analysis (PCA) to evaluate the physical stability of the amorphous samples. Results emphasized that optimal physical stability was achieved when amorphous solids were prepared at a precipitation temperature of 10 °C and a filter cake thickness of 4 cm. Moreover, the integration of PDF analysis with Rc values was confirmed as an innovative approach for assessing physical stability, thus offering enhanced efficiency and accuracy over conventional accelerated stability testing methods.

The Optimization of Pair Distribution Functions for the Evaluation of the Degree of Disorder and Physical Stability in Amorphous Solids

“…Hence, the utilization of PXRD, PDF, and PCA techniques offer significant benefits in the precise and efficient evaluation of the degree of disorder and physical stability in amorphous drugs, as compared to an accelerated stability test. Moreover, by using this method, we have quickly and accurately evaluated the amorphous solids' physical stability in nilotinib free base, which were prepared under different precipitation conditions [41][42][43].…”