Does the γ Polymorph of Glycine Nucleate Faster? A Quantitative Study of Nucleation from Aqueous Solution

We quantitatively study the crystallization of glycine from solution by following the crystallization of a plate with 96 wells, each with 0.1 mL of supersaturated solution. Our first aim is to address the difficult problem of obtaining nucleation data that is reproducible. This problem is difficult because of the extreme sensitivity of nucleation times. Nucleation is sensitive to factors that include how the crystallizing system is prepared and even small (1%) variations in the supersaturation. We discuss the appropriate statistical tests needed to show reproducibility. Our second aim is to study the competition between the nucleation of the alpha and gamma polymorphs of glycine. We find that nucleation appears to be heterogeneous: Some samples crystallize in minutes, whereas others do not crystallize after days, which indicates that there is no well-defined nucleation rate for the set of samples. Homogeneous nucleation gives a well-defined rate. Those samples that crystallize in minutes mostly yield the metastable alpha polymorph. We speculate that these crystals may be the result of seed crystals formed by transient local increases in supersaturation in pipette tips during sample preparation. However, those that crystallize in hours are largely the equilibrium gamma polymorph. This is perhaps surprising because typically the alpha polymorph is obtained from crystallization from aqueous solutions near neutral pH. We speculate that the nucleation rate of the gamma polymorph may be higher than that of the alpha form but that in earlier work with larger solution volumes (increasing the probability of seeding) and with stirring the alpha polymorph dominates because of its much faster growth rate.