New polymorph discovery and spherical morphology engineering of triglycine crystals

Triglycine (GGG), owing to its simple structure and well-defined hydrogen-bonding network, has become a representative model molecule in the fields of peptide coordination chemistry, bioconjugation, and drug delivery. However, the solid-state applications of this compound have long been constrained by its property uncertainty arising from polymorphism and extremely poor processability caused by anisotropic crystal habits. In this work, a new anhydrous polymorph (Form II) is reported for the first time, and its crystal structure is solved by single-crystal X-ray diffraction. The results demonstrated that the two anhydrous forms (Forms I and II) exhibit comparable thermodynamic stability and remain stable under both mechanical grinding and solution-mediated slurry conditions. In addition, spherical crystalline of GGG Form 2H were successfully obtained for the first time via antisolvent crystallization in a tetrahydrofuran system. The effects of the polymeric additives hydroxypropyl methylcellulose and polyvinylpyrrolidone on the sphericity, particle size distribution, and powder flowability of the spherical aggregates were systematically investigated. The aggregation mechanism of the spherical particles and the regulatory role of additives were further elucidated. This study provides new insights into the interplay among solvent environment, polymorphism, and crystal morphology, and offers a feasible strategy for morphology control of tripeptides