Computational insights into drug hygroscopicity by coupling machine learning and molecular simulation.

Hygroscopicity is one of the critical material attributes (CMAs) of active pharmaceutical ingredients (APIs), and excessive hygroscopicity can adversely affect drug manufacturability, stability, and even therapeutic efficacy. Traditional experimental methods for measuring hygroscopicity are time- and resource-consuming, limiting their suitability for the growing demands of preformulation developability screening. Therefore, developing robust, high-throughput computational approaches to identify highly hygroscopic compounds is of great significance for drug screening, formulation design, and risk management. Here, we propose an integrated computational strategy that combines machine learning (ML) and molecular simulations for rapid prediction of drug hygroscopicity and mechanistic elucidation. A dataset comprising dynamic vapor sorption (DVS) curves for 607 drugs was first curated, based on which 8 ML algorithms representing different modeling principles were compared. Among them, Tabular Prior-data Fitted Networks (TabPFN) achieved the best performance, with an R2 of 0.701 ± 0.075 for regression of moisture-induced weight change (%), and accuracies of 0.741 ± 0.047 and 0.872 ± 0.029 for four-class and binary classification. SHapley Additive exPlanations (SHAP) analysis identified molecular surface area, polarity, and electrostatic descriptors as key factors influencing hygroscopicity. Building upon this insight, molecular dynamics and quantum chemical simulations further revealed that polar functional groups, hydrogen bonding, and surface conformations govern water-molecule interactions, consistent with the ML-derived insights. Overall, the effective combination of AI-driven predictions and physics-based mechanistic insights underscores the potential of this approach for preformulation developability screening and optimization, offering a promising avenue to reduce R&D costs and enhance drug development efficiency.