Principal Scientist Genentech Inc. South San Francisco, California
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. To address this need, we’d like to present and discuss our recent development of a high-throughput screening (HTS) workflow for assessing amorphous solubility and crystallization risk of API with different ASD excipients. Specifically, we used a robotic liquid handler to achieve automated preparation of a concentration series of samples, which were then transferred to kinetic turbidity measurement in the microplate format. The data were efficiently processed by in-house R scripts, allowing for high-throughput analyses of amorphous solubility as well as excipient performance by profiling turbidity trace lines.
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, including crystallization, amorphous precipitation, and nanoparticle formation. 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.
Learning Objectives:
Upon completion, participant will be able to understand how different excipient choices can impact ASD formulation performance.
Upon completion, participant will be able to value how high-throughput approaches can facilitate early-stage ASD excipient screening and formulation development.
Upon completion, participant will be able to develop and use similar workflows to address their challenges in formulation screening and optimization.