Mechanism-Driven Reaction Design: Development and Application of Non-Linear Hazardous Reaction via Mechanism-Oriented Kinetic Analysis

Given the recent rapid advances in computational technology, kinetic modeling of chemical reactions has emerged as a powerful technique for reaction analysis and control. Meanwhile, detailed understanding of reactions and processes is an upcoming issue in modern process development in the pharmaceutical industry. Since the quality by design (QbD) approach has been introduced by ICH guidelines, predictive and quantitative reaction analysis is expected in designing chemical process by regulatory agencies, to achieve better quality-controlled medication and social acceptance. Consequently, numerical simulation utilizing reaction kinetic model is attracting broad interest due to its unique capability of extrapolation in prediction rooted in the nature of physical model. However, the kinetic modeling and simulation of organic reactions remain significantly more challenging than modeling efforts in other fields that utilize well-established physical or semi-empirical models, since these require ‘full-scratch’ model building based on a detailed theoretical and experimental understanding of rate laws for each chemical reaction, which inherently have unique mechanisms, namely, unknown models. In this paper, extensive example of practical application of kinetic modeling and simulation in reaction development and scale-up based on physical organic chemistry approach are presented, particularly from the aspect as a tool for synthetic organic chemists.