Solvent-free modafinil acid cocrystallization through a green melt-based approach

Abstract

This study presents a rational crystal engineering strategy for the accelerated, solvent-free preparation of pharmaceutical cocrystals utilizing an integrated approach that combines predictive machine learning (ML) screening with a melt-based Kofler contact strategy. This strategy was applied to modafinil acid, a poorly water-soluble intermediate essential for the synthesis of modafinil and adrafinil. By leveraging thermodynamic principles and process intensification, we developed a solvent-free quantitative method for preparing modafinil acid cocrystal hydrates, successfully eliminating hazardous waste streams. This study bridges sustainable cocrystal design with solvent-free synthesis by integrating quantitative eutectic phase analysis, thereby enabling efficient cocrystal preparation and minimizing conventional trial-and-error screening. Molecular analysis elucidates the intermolecular interactions governing phase stability, while solid-state characterization confirms a four-fold increase in aqueous solubility and a 1.5-fold improvement in phosphate buffer. This integrated workflow offers an efficient, environmentally benign route for the sustainable synthesis of pharmaceutical cocrystals by balancing predictive digital tools with rapid experimental validation.