Modeling-based Development of an Enantioselective Hydrogenation Reaction of a Sitagliptine Intermediate

This work presents a quality by design (QbD) driven approach to the plan of experiments and reaction modeling that was effective in obtaining enhanced process knowledge and defining a design space for an active pharmaceutical ingredient (API) manufacturing process. Engineering aspects of the process were explored by process modeling using computer predictive process simulators. QbD approach is presented on a case study of the process development of the sitagliptine synthesis step. The process involves an enantioselective hydrogenation step. Based on the proposed reaction mechanism and by combining the heat and mass transfer, thermodynamics, and the kinetics of the reactions, the API quality specifications (enantiomeric purity, impurity levels) are described across the modeling of process space. This process space was defined through target specifications, practical operating conditions for scale-up, and plant control capabilities. Model predictions were verified with results obtained in the laboratory, and at pilot plant scale.