Applications of Quantum Chemistry in Pharmaceutical Process Development: Current State and Opportunities

Application of computational methods to understanding and predicting properties of analogues for drug discovery has enjoyed a long history of success. However, the drug development space (post-candidate selection) is currently experiencing a rapid growth in this arena. Due to the revolution in computing hardware development and improved computational techniques, quantum chemical (QC) calculations have become an essential tool in this space, allowing results from complex calculations to inform chemical development efforts. As a result, numerous pharmaceutical companies are employing QC as part of their drug development workflow. Calculations cover the range of transition state calculations, reaction path determination, and potential energy surface scans, among others. The impact of this rapid growth is realized by providing an in-depth understanding of chemical processes and predictive insight into the outcome of potential process routes and conditions. This review surveys the state of the art in these drug development applications in the pharmaceutical industry. Statistics of computational methods, software, and other metrics for publications in the last 14 years (2005–2019) are presented. Predictive applications of quantum chemistry for influencing experiments in reaction optimization and catalyst design are described. Important gaps in hardware and software capabilities that need to be addressed in order for quantum chemistry to become a more practical and impactful tool in pharmaceutical drug development are discussed. Perspectives for the future direction of application of QC to pharmaceutical drug development are proposed.