Investigation of Metastable Zones and Induction Times in Glycine Crystallization across Three Different Antisolvents

Experimental data on the effects that different antisolvents and antisolvent addition strategies have on nucleation behaviour in antisolvent crystallisation is very limited and our understanding of these effects is sparse. In this work we measured the metastable zone width for the isothermal antisolvent crystallisation of glycine from water utilising methanol, ethanol and dimethylformamide as antisolvents. We then investigated induction times for glycine crystallisation across these metastable zones using the same three antisolvents. Supersaturated solutions were prepared by mixing of an antisolvent with undersaturated aqueous glycine solutions, either by batch rapid addition or using a continuous static mixer. Induction times were then recorded under agitated isothermal conditions in small vials with the use of webcam imaging and vary from apparently instant to thousands of seconds over a range of compositions and different mixing modes. Well defined induction times were detected across most of the metastable zone which shows that primary nucleation is significant at much lower supersaturations than those identified in conventional metastable zone width measurements. As supersaturation increases towards metastable zone limit, crystal growth and secondary nucleation are likely to become rate limiting factors in observed induction times for antisolvent crystallisation. Furthermore, the observed induction times were strongly dependent on the mode of mixing (batch rapid addition vs continuous static mixing), which demonstrates an interplay of antisolvents effects on nucleation with their effects on mixing, leading to cross-over of mixing and nucleation timescales. This shows that appropriate mixing strategies are crucial for the rational development of robust scalable antisolvent crystallisation processes.