Analysis of the Change in Molecular Complexity of Reaction Products in Process Development Activities at AstraZeneca Over Time

The assessment of molecular complexity of active pharmaceutical ingredients (APIs) can help guide decisions within drug development, for example, by correlation to sustainability targets, project resource requirements, and predicted development and manufacturing timelines. However, such quantifications are limited by the challenge of defining complexity itself as well as the small sample size of API molecules making longer term comparisons challenging. We have used four complementary approaches to calculate the complexity of reaction products of more than 165,000 reaction entries across our process development electronic laboratory notebooks. Importantly, this dataset covers both intermediates, APIs, and other molecules requiring synthesis, thus, attempts to provide an analysis of reaction products from all our synthetic chemistry activities. This information facilitated the investigation of changes in the mean values of different measures of molecular complexity per year between 2007 and 2020. We discuss the insights these quantifications reveal and how this analysis may be of more general use in understanding the diversity of the molecules in our process development portfolio.