Exploration of glycyl-L-valine spherulites: Solvent-induced control over nonclassical crystallization pathways

Glycyl-L-valine (GLV) is a potentially biologically active dipeptide composed of glycine and L-valine, which exhibits diverse antioxidant, anti-inflammatory, and cytoprotective properties. GLV crystals typically form needles and flakes, morphologies that may negatively impact dissolution rate, flowability, filtration, and formulation processes. For the first time, this study reports the successful preparation of spherical crystal of GLV. Spherical crystals with superior filtration efficiency, powder flowability, and bulk density were obtained in tetrahydrofuran (THF) and dioxane. The formation mechanism of GLV spherical crystals in THF was revealed: solvent-induced crystalline defects trigger non-crystallographic branching, enabling further growth into spherulites. The results demonstrate that solvent-induced non-crystallographic branching produces GLV spherical crystals with improved bulk density, flowability, compactibility, and humidity stability. The formation of GLV spherulites is governed by the synergistic interplay of intermolecular hydrogen bonding and hydrophobic interactions, establishing this system as an ideal model for elucidating non-classical crystallization pathways in short peptides. These findings provide a robust theoretical framework for the rational design of novel biomaterials.