(613c) Development of a Cryogenic Flow Synthesis and Continuous Extraction Process with Enhanced Yield, Process Control, and Greenness.

The use of continuous processing in pharma can provide opportunities to access novel reaction conditions, reduce environmental impact, control impurities, and improve yield through process intensification. To this end, this talk focuses on the development of a novel process for obtaining high quality drug substance (DS) and process yields through the implementation of a cryogenic plug flow reaction and continuous counter-current extraction for a small-molecule drug candidate. The original pharmaceutical process featured a flow synthesis in organic solvent to form the DS, followed by a series of low-yielding batch extractive aqueous washes to remove key process impurities, and a crystallization. To improve greenness and mitigate solubility issues, eliminate a potential nitrosamine risk, and improve reaction control during manufacturing, the flow reaction was re-engineered by swapping the solvent system from the environmentally harmful dichloromethane to toluene and methanol, removing organic base, and extending the reaction time. Online PAT was also implemented to have better control over reaction stoichiometry. To control several key impurities including a dimer-like Michael adduct impurity, a continuous multi-stage counter current extraction was developed featuring aqueous acidic treatment and pH control to remove key impurities, followed by a co-current aqueous basic treatment to neutralize the organic product solution. Through both lab experimentation and model development, a robust control strategy was implemented to be able to both tune the product purity and yield through manipulating the pH at each stage. The use of a continuous extraction resulted in a 10% yield increase compared to the prior batch process. This process and control strategy was successfully scaled at an external CMO to deliver 200 kg of DS.