High-throughput kinetic turbidity analysis for determination of amorphous solubility and excipient screening for amorphous solid dispersions

Abstract

Many poorly water-soluble active pharmaceutical ingredients (APIs) rely on supersaturating formulations, such as amorphous solid dispersions (ASDs), to enhance oral bioavailability. ASDs kinetically trap amorphous solid drugs within polymer excipient matrices to maintain the amorphous drug states. The maximum solution concentration of the API in these formulations is known as the amorphous solubility. In early drug development with scarce material and time, high-throughput approaches to measuring amorphous solubility and screening excipient effects on crystallization risk offer significant benefits to preclinical formulation scientists. Here, we developed a high-throughput screening (HTS) workflow to quantify amorphous solubility and screen ASD excipients by automated kinetic turbidity analysis. Testing 20 model APIs with a wide range of biorelevant solubility, we demonstrated their apparent amorphous solubility determined by the HTS approach strongly correlated with quantification results using conventional liquid chromatography; while the real-time analysis significantly saved analytical time and experimental efforts. Furthermore, kinetic turbidity profiles elucidated distinct excipient effects on the precipitation process of APIs. These results were successfully translated to dissolution and precipitation behaviors of ASD formulations composed of the tested polymers. The high-throughput kinetic turbidity workflow presents a facile and information-rich approach for amorphous solubility screenings against excipients, and helps guide enabling formulation development.