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

Abstract

We quantitatively study the crystallisation of glycine from solution, by following the crystallisation 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 due to the extreme sensitivity of nucleation times. Nucleation is sensitive to factors that include how the crystallising 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 crystallise in minutes, while others do not crystallise 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 crystallise 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 crystallise in hours are largely in the equilibrium gamma polymorph. This is perhaps surprising as typically the alpha polymorph is obtained from crystallisation 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.

Nucleation kinetics for primary, secondary and ultrasound-induced paracetamol crystallization

“…Maintenance was carried out on the UP50H processor between experiments. The two-sample Kolmogorov-Smirnov test 34,35 indicated that it is unlikely that this affected the performance of the probe between experiments. This is discussed in Subsection S1.2 Impact of UP50H maintenance in the SI.…”

Molecular dynamics simulations of aqueous glycine solutions

“…4 The nucleation and crystal growth of α-and γ-glycine from the same solution have been investigated experimentally. 6 Little et al 6 concluded that the rate of nucleation is very sensitive to impurities, the conditions in which the samples are prepared and supersaturation. The least stable β-glycine polymorph crystalizes from aqueous solutions containing methanol or ethanol 7 or from the gas phase via sublimation of the α or γ forms in vacuum.…”

Interfacial Concentration Effect Facilitates Heterogeneous Nucleation from Solution

“…A number of different microfluidic devices − have been developed for the purpose of investigating crystallization behavior. These devices have been used to investigate the nucleation of water, proteins, , and small organic molecules. , Another small scale experimental setup uses a microplate to store a large number of small volumes of solutions , to observe their crystallization behavior. As these are open to the air, the solution is typically covered by oil to prevent evaporation, similarly to microfluidics, where immiscible liquid is used to separate microdroplets.…”