Uncovering a Hidden Polymorph of <scp>l</scp> -Serine through Additive-Mediated Crystallization

A new polymorph of l-serine (form V) was discovered via additive-mediated crystallization under ambient pressure─only the second anhydrous form obtained without the need for high-pressure conditions. Its structure features zwitterionic dimers stabilized by N–H···O and O–H···O hydrogen bonds, resembling the hydrate form to some extent but lacking solvent incorporation. This might indicate a solvent-mediated nucleation mechanism. Periodic DFT calculations show that form V is more stable than that of form I at 0 K, but Gibbs free energy and entropy analysis indicates a temperature-dependent crossover, with form I favored at higher temperatures. These findings underscore the role of supramolecular assembly and solution conditions in polymorph formation, emphasizing the need for combined structural and thermodynamic analysis.