In this work DLS, NTA, SAXS and NMR were used to investigate populations, size distributions and structure of clusters in undersaturated aqueous solutions of glycine. Molecular and colloidal scale (mesoscale) clusters with radii around 0.3-0.5 nm and 100-150 nm, respectively, were observed using complementary experimental techniques. Molecular clusters are consistent with hydrated glycine dimers present in equilibrium with glycine monomers in aqueous solutions. Mesoscale clusters previously observed in supersaturated glycine solutions appear to be indefinitely stable, in mutual equilibrium within mesostructured undersaturated solutions across all glycine concentrations investigated here, down to as low as 1 mg/g of water.

Glycine polymorphism presents a conundrum: while the metastable α form of glycine typically crystallises in bulk cooling crystallisation from aqueous solution, both the highly unstable β and stable γ forms can be selectively crystallised in small scale cooling or evaporative experiments, without any additives, cosolvents or external fields. Small scale experiments in microwells or droplets differ from bulk crystallisation in some key aspects: absence of agitation, presence of large (and often very particular) surface areas per crystallisation volume, and ability to reach very high supersaturations. In this work we investigated effects of agitation on polymorphic outcomes in glycine crystallisation from aqueous solutions across a wide range of supersaturations at mL scale under quiescent conditions with and without a PTFE-coated magnetic stirrer (without any stirring) as well as under stirred conditions (with agitation supplied by the stirrer). In the absence of stirring, γ was predominant at higher glycine concentrations, which indicates that γ is more likely to nucleate than α in highly supersaturated aqueous solutions under quiescent conditions. Intriguingly, we found that under stirred conditions α was predominant at all concentrations and temperatures investigated. The effect of stirring on the preference for α glycine polymorphism cannot be fully explained by secondary nucleation alone. Instead, primary nucleation of glycine (at least of metastable forms) is strongly enhanced by stirring, in agreement with previous observations of shear effect on primary nucleation of glycine, and it is likely that similar effects play a role in other polymorphic systems of pharmaceutical interest. † Raw data is available open access through the following DOI: https://doi.org/ 10.15129/9a4ec7f5-fe41-4ec2-92ef-a9abca03b217 ‡ Electronic supplementary information (ESI) available: Contains information about quenched cooling experiments and movement induced nucleation. See

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