(15g) Reaction Screening in an Automated Droplet Screening System for Pharmaceutical Process Development

Pharmaceutical companies are increasingly incentivized to reduce the time to bring a drug to market. Automation offers one means to speeding up drug discovery and process development activities. For process development, it is important that reaction screening be performed in systems that allow for exploration of mass and heat transfer phenomena and for the extraction of intrinsic reaction kinetics. Droplet microfluidic screening systems, which allow for easy interchange of reagents and for precise control of temperature and mixing rates at micro- and millimeter length scales, have attracted recent attention in this space. Here, we describe the development and evaluation of an automated screening system focused on scalability and applicability towards a wide range of chemistries. Our system performs reactions at a 10-100 µl scale in droplets that are prepared by a retrofitted commercial autosampler controlled with LabVIEW. Droplets are transferred into a pressurized and heated reactor where reaction occurs. Oscillation of the droplet during the reaction provides thorough mixing and a tunable residence time. Crude reaction mixtures are diluted automatically and a second commercially modified HPLC performs online analysis and fraction collection with results being processed and exported automatically. The automated system is demonstrated by identifying optimal temperature, solvents, additives, and equivalencies for a deprotection reaction. The results are compared to a milliliter-scale batch screening methodology and to an automated reaction screening system using desorption electrospray ionization mass spectrometry.