Using PAT To Understand, Control, and Rapidly Scale Up the Production of a Hydrogenation Reaction and Isolation of Pharmaceutical Intermediate

The development of a hydrogenation process and subsequent isolation for an intermediate in the manufacture of an active pharmaceutical ingredient is described. In-line process analytical technology (PAT) approaches were applied to gain process understanding and control. First, a calibration-free, qualitative, scale-independent approach using in situ mid-infrared (MIR) spectrometry to determine the end point of a hydrogenation reaction in real time is described. A curve-fitting algorithm was developed using MATLAB software to allow the reaction rate to be calculated at any given time during the reaction on the basis of the consumption of an intermediate species. The algorithm, coupled with understanding of the process, allowed the end point to be correctly identified in triplicate during scale-up of the process from 0.2 to 20 L scale. Second, a quantitative partial least-squares (PLS) regression model was developed using near-infrared (NIR) spectrometry to determine the solvent composition during the subse...