Application of Computational Chemistry in Pharmaceutical Process Development

Increasing speed of drug discovery and chemical development often requires complementing experimental data with a variety of modeling tools to provide fundamental knowledge at a molecular level. With advances in computational power and theoretical techniques (e.g. density functional theory), implementation of quantum mechanical (QM) calculations for systems relevant to small molecule pharmaceutical process development has become more readily available. Process design and understanding in several areas of chemical development are significantly enhanced by utilization of QM modeling. In this work, several industrially relevant case studies will be presented to provide an overview of QM modeling and its applications in both early and late phase development. The case studies will discuss QM calculations in three key areas related to reaction and crystallization development: a) evaluation of relative stabilities and activation energies (pKa estimation, conformational analysis, transition structures); b) investigation of parallel reaction pathways (chemo- and stereo-selectivities); c) spectral predictions for reactive intermediates (NMR, FTIR, Raman). Impact to process understanding and design gained from computational chemistry modeling will be highlighted.