Practical Computational Exploration of Chemical Reaction Space: Assessing the Chemical Stability of Active...

Understanding the chemical degradation of active pharmaceutical ingredients is critical for formulation development and regulatory compliance, yet computational tools either rely on predefined reaction rules that limit discovery of unanticipated pathways or cannot distinguish energetically accessible products from formally possible ones. We present an automated workflow requiring no predefined reaction rules that explores degradation networks from the potential energy surface. The approach combines metadynamics for reaction discovery, energy- and count-based filtering, density functional theory refinement, and microkinetic modelling to calculate time- and temperature-dependent product distributions. Applied to the acid-catalysed degradation of BMS-644950, the workflow constructs a network of 1720 species and 2471 elementary steps, reduced to 8 degradation products. Microkinetic simulations identify the two observed lactone products as dominant and propose a tentative structure for a previously uncharacterised 466 Da impurity (R. Hemingway et al., Organic Process Research & Development 28 (2024): 674-692). The calculations reveal that several thermodynamically favourable products remain unobserved because activation barriers of 36-40 kcal  ${\mathrm{mol}}^{-1}$ render them kinetically inaccessible on the experimental timescale, a distinction reaction-rule-based methods cannot make. The exploration finishes within 3 days on a compute cluster, demonstrating that automated, physics-based degradation modelling is tractable for drug-like molecules at industrially relevant scales.