Reaction kinetics determination and uncertainty analysis for the synthesis of the cancer drug lomustine

Abstract

Fast and reliable model development frameworks are required to support current trends in modernization of pharmaceutical processing, promoting the use of digital platforms to assist process design and operation. In this work, we use a parameter estimation framework built into the PharmaPy library to determine rate parameters and uncertainty regions of different mechanistic and semi-empirical kinetic expressions for the synthesis of the drug lomustine. The parameter estimation procedure was complemented by identifiability analysis, resulting in simplified reaction mechanisms. Comparison of parameters and their uncertainty in process design was demonstrated through design space analysis, showing important differences in model prediction and the extent of their corresponding design spaces. The results of this work can serve to analyze lomustine manufacturing processes that include separation and isolation steps, where parametric uncertainty is expected to propagate along the manufacturing line and impact process feasible operation, and attainment of critical quality attributes of the product.