Computationally assisted and inherently safer solvent screening for solution crystallization with experimental validation

Background Solvent selection is a decisive step in solution crystallization, yet current methods remain constrained by limited-scale solubility screening and focus primarily on solubility, with safety and environmental considerations deferred until after solubility-based preselection. Methods This work proposes an integrated computational solvent screening framework for solution crystallization that simultaneously considers solubility and environmental–health–safety (EHS) indices. Aspirin crystallization is used as a case study to demonstrate the applicability of the framework. A large-scale preliminary screening of more than 8000 organic solvents is first conducted using predicted EHS indicators. Subsequently, the solubilities of the candidates satisfying the predefined EHS criteria are calculated by solving the solid–liquid equilibrium (SLE) and are used to estimate the theoretical crystallization yield and solvent equivalent mass. Candidates meeting the predefined crystallization-performance criteria are further assessed using experimentally reported EHS properties and practical considerations. Methyl 3-methoxypropionate (MMP) is subsequently selected as a representative solvent for experimental validation. Significant Findings The proposed framework provides a practical workflow for crystallization solvent selection by integrating large-scale EHS screening, solubility evaluation, and post-screening practical assessment. The aspirin case study supports its utility by identifying and validating MMP as a promising solvent candidate with a balanced crystallization-performance and process-safety profile.