Mechanistic Insights into Molecular Modifiers That Promote Urate Crystallization through Solute Assembly Regulation

Understanding crystallization modifier mechanisms remains a central challenge in crystal engineering, particularly for growth promoters whose modes of action are far less understood than inhibitors. Here, we investigate riboflavin (RF) as a crystallization promoter for ammonium urate (NH4HU) using combined microfluidic experiments and molecular dynamics simulations to elucidate its underlying mechanism. We discovered that RF reorganizes neighboring urate ions into growth-compatible coplanar conformations, contrasting with their naturally preferred growth-incompatible stacked arrangements. This identifies a solution-phase preassembly mechanism for enhancing crystal growth, distinct from classical monomer addition or traditional surface-based pathways. We found that the modifier’s ability to reorganize surrounding urate correlates with its aromatic ring size, explaining why the large RF framework exhibits unique promotion effects among known modifiers. Guided by detailed contact analysis between RF and urate ions, we rationally designed RF derivatives with enhanced promotion capabilities and experimentally validated their predicted performance, with the natural metabolite lumichrome showing a 40% growth enhancement compared to the 20% enhancement observed for RF. Our findings establish solution-phase preorganization as a viable mechanism for crystallization control.