Multiscale Insights into Deuterated Glycine Crystallization

The effect of deuteration on crystallization is under discussion. Glycine is a model system extensively investigated because of discrepancies in the literature, particularly on the appearance of γ-glycine in heavy water. In this study, we combined single crystal nucleation spectroscopy (SCNS) and bulk crystallization to systematically investigate the effect of deuteration on glycine crystallization. SCNS results showed that deuterated glycine (d-glycine) in heavy water crystallizes via a nonclassical nucleation pathway, as observed in water. In these experiments, however, γ-d-glycine was never observed. β-d-glycine appears first, but quickly disappears while α-d-glycine grows. Statistical analysis revealed that β-d-glycine in D2O was more stable than β-glycine in H2O. Bulk crystallization experiments revealed that the γ-polymorph can be observed when the nucleation rate is high in both H2O and D2O. The major difference between them is the stability of the β-polymorph in D2O. Differential scanning calorimetry (DSC) and thermogravimetric (TG) experiments demonstrated that β-d-glycine is more stable than β-glycine, which can be explained by higher hydrogen-bonding strength because of deuteration. These findings suggest that deuteration increases the stability of β-glycine, possibly facilitating γ-glycine formation. This study provides new insights into the role of solvent isotope effects on crystallization toward rational polymorph control.