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.

Most substances can crystallise into two or more different crystal lattices, called polymorphs. Despite this, there are no systems in which we can quantitatively predict the probability of one competing polymorph forming, instead of the other. We address this problem using large scale (hundreds of events) studies of the competing nucleation of the alpha and gamma polymorphs of glycine. In situ Raman spectroscopy is used to identify the polymorph of each crystal. We find that the nucleation kinetics of the two polymorphs is very different. Nucleation of the alpha polymorph starts off slowly but accelerates, while nucleation of the gamma polymorph starts off fast but then slows. We exploit this difference to increase the purity with which we obtain the gamma polymorph by a factor of ten. The statistics of the nucleation of crystals is analogous to that of human mortality, and using a result from medical statistics we show that conventional nucleation data can say nothing about what, if any, are the correlations between competing nucleation processes. Thus we can show that, with data of our form, it is impossible to disentangle the competing nucleation processes. We also find that the growth rate and the shape of a crystal depends on when it nucleated. This is new evidence that nucleation and growth are linked.

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