Solvent-Free Modafinil Acid Cocrystallization through 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 the melt-based Kofler contact strategy. The 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 preparation of modafinil acid cocrystal hydrates, successfully eliminating hazardous waste streams. In turn, this paper further bridge sustainable practice of rational cocrystal design with solvent-free synthesis and navigating quantitative eutectic phase analysis converge intensive cocrystal preparation that eliminates traditional trial-and-error screening. Molecular analysis elucidates the intermolecular interactions governing phase stability, while solid-state characterization confirmed 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, balancing predictive digital tools with rapid experimental validation.