Understanding How Synthetic Impurities Affect Glyphosate Solubility and Crystal Growth Using Free Energy Calculations and Molecular Dynamics Simulations

Glyphosate, the most widely used herbicide worldwide, crystallizes through complex intermolecular interactions that are strongly influenced by synthesis-derived impurities. Understanding this process at the molecular scale is critical for optimizing production, ensuring product quality, and assessing the environmental impact. Here, we employ direct coexistence molecular dynamics simulations and free energy calculations to elucidate how glycine─a prevalent synthesis byproduct─modulates glyphosate solubility and crystal growth in aqueous solutions. Our simulations identify two major mechanisms by which glycine hinders crystallization. First, direct coexistence simulations show that glycine preferentially adsorbs at crystal surfaces, hindering glyphosate attachment and slowing growth. Second, free energy calculations demonstrate that glycine enhances glyphosate solubility, reducing the supersaturation driving force to incorporate into the crystal phase. Experimental measurements corroborate our predictions, confirming both enhanced solubility and reduced crystallization kinetics in the glycine-bearing systems. These findings establish that glycine─typically considered an inert impurity─actively disrupts glyphosate crystallization by promoting its dissolution. More broadly, this integrated computational-experimental approach highlights the power of molecular simulations to disentangle impurity effects, interfacial phenomena, and solution thermodynamics in crystallization, providing molecular-level insights for optimizing industrial protocols and predicting agrochemical behavior under relevant environmental conditions.