Theoretical and Experimental Assessment of Nitrosamine Risk in Industrial Solvent Recovery

The recovery of solvents in pharmaceutical manufacturing offers substantial sustainability benefits but raises concerns about the potential carryover of mutagenic impurities, particularly N-nitrosamines (hereinafter: nitrosamines). This study presents a validated, comprehensive framework for in-silico assessment of nitrosamine risk in industrial solvent recovery processes by distillation. Its application was demonstrated exemplarily using three small molecule nitrosamines and 32 commonly used solvents. The proposed procedure consists of vapor–liquid equilibria (VLE) prediction, followed by risk estimation using a newly introduced key performance indicator (KPI), and detailed risk assessment using process simulation. Two state-of-the-art methods for nitrosamine-solvent VLE prediction were tested and successfully validated. The average relative volatility (ARV), as a KPI for separation efficiency, was shown to be suitable for estimating the risk of nitrosamine-solvent combinations. A Monte Carlo simulation demonstrated that ARVs ≥3 reliably predict nitrosamine purge factors exceeding 1000, supporting safe reuse in most cases. Nitrosamine risk for specific recovery processes can be assessed quantitatively by obtaining nitrosamine purge factors from process simulation. In a case study, this procedure was applied to an industrial acetonitrile recovery process, showing complete nitrosamine removal. Lab-scale distillations confirmed these findings. Overall, the results support a science-based, process-specific risk assessment strategy for solvent recovery, addressing regulatory concerns and enabling safer, more sustainable practices.