(542c) Crystal Growth and Secondary Nucleation in the Metastable Zone

Crystallization from solution is a purification process used throughout the pharmaceutical and chemical industries to achieve desired crystalline particulate product properties, such as solid form, particle size, shape and purity. Control over these particulate properties facilitates downstream processing and resulting product performance. To achieve control of such a crystallization process, an understanding of nucleation and growth, the two fundamental stages of crystal formation, is required.

In order to avoid problems associated with the intrinsic stochasticity of primary nucleation, secondary nucleation, the generation of new crystal nuclei from already-existing crystals, is often employed in industrial crystallization. Secondary nucleation is often initiated at relatively low supersaturations to provide a controlled, steady supply of new crystals, accompanied by relatively slow crystal growth to achieve good purification and consistent process performance. This study aims to improve fundamental understanding of the relationships between crystal growth, secondary nucleation and supersaturation in the metastable zone for crystallization of α-glycine from aqueous solutions.

Methods

Nucleation and growth kinetics of α-glycine were determined experimentally using the Crystalline instrument from Technobis which uses imaging and transmission measurements to monitor crystallization experiments. The instrument holds 8 individual agitated vials within individual chambers, each allowing specific heating and cooling profiles to be implemented. This allows a rapid assessment of the crystallization phenomena and their dependence on process conditions. To illuminate the link between primary and secondary nucleation and crystal growth, seeded and unseeded experiments in identical conditions were run in parallel. In each seeded experiment, a single seed crystal was prepared using cooling crystallization, sized using optical microscopy and added to the experimental vessel as previously outlined¹. Nucleation and growth kinetics were investigated under isothermal conditions at 25°C for a range of solution supersaturations in agitated vials. Metastable zone widths were determined at various cooling rates to determine a range of supersaturations where primary nucleation was sufficiently slow at 25°C. The solubility of α-glycine was measured at various heating rates and was in good agreement with data reported by Rowlands². Induction times were measured under isothermal conditions for relative supersaturations S up to 1.2, in order to estimate primary nucleation kinetics and establish a time window for single crystal seeding. In both seeded and unseeded experiments, particle number densities were estimated from in situ imaging once numbers of crystals in images exceeded a baseline threshold. The secondary nucleation rate B was estimated from the initial rate of change of the particle number density. Crystal growth kinetics were also estimated from in situ imaging.

Results and Discussion

Crystal growth rates for α-glycine estimated from in situ imaging were in good agreement with values reported in literature from single crystal growth experiments. Plotting growth rates on a linear scale appears to indicate the presence of a ‘dead zone’ below a certain supersaturation, where growth does not seem to take place. However, if data is plotted on a log-log scale, they show a clear power law dependence on supersaturation, as may be expected from crystal growth theories. Therefore there does not appear to be any dead zone for crystal growth of α-glycine.

Secondary nucleation rates for both seeded and unseeded experiments were also estimated from in situ imaging. When shown on a linear scale, data seem to indicate a secondary nucleation threshold around S=1.1 (Figure 1a). Again, when data is shown on a log-log scale, they are consistent with a power law dependence on supersaturation. Although it cannot be ruled out that secondary nucleation completely ceases at some lower supersaturations, it can become too slow to measure with a given experimental technique at some point, and it can also become insignificant in a practical industrial crystallization context. Furthermore, secondary nucleation rates in seeded and unseeded experiments were very similar (Figure 1b), which is consistent with the concept of the ‘single nucleus mechanism’³: in other words even in unseeded conditions, crystallization proceeds through the formation of a single crystal seed from solution by primary nucleation, with further nuclei then appearing through secondary nucleation from this original seed crystal.

Crystal growth and secondary nucleation are often studied and presented as two conceptually separate processes or mechanisms. Our approach allows us to directly compare the growth rate and the corresponding secondary nucleation rate from the same experimental vials, based on the same imaging-based measurement and image analysis. In Figure 2 we show that there is a close relationship between growth and secondary nucleation kinetics across a wide range of supersaturations. This suggests a possible mechanistic relationship between the two phenomena, where the secondary nucleation induced by fluid shear is related to growth of the crystal boundary layer in contact with the supersaturated solution, where loosely bound crystalline domains are swept from the boundary layer and serve as crystal nuclei. This effect would be clearly distinct from mechanical breakage or attrition of seed crystals, as there is no reason why such a mechanical process would be related to the crystal growth rate and indeed solution supersaturation.

Conclusions

Using a rapid small scale experimental technique utilizing image analysis to quantify nucleation and growth kinetics, the metastable zone, primary and secondary nucleation kinetics and growth rates of α-glycine has been investigated. Results show that there is neither crystal growth dead zone nor secondary nucleation threshold present in this system. It is also shown that there is a close relationship between the secondary nucleation and the crystal growth rate across all supersaturations investigated. This work will provide better understanding of crystal nucleation and growth mechanisms while using rapid, small scale experiments and data analysis illustrated here should enable more facile crystallization process development.

References

(1) Maria L. Briuglia, Jan Sefcik, J. H. ter H. Measuring Secondary Nucleation through Single Crystal Seeding. Cryst. growth Des. 2019.

(2) Rowland, D. Thermodynamic Properties of the Glycine + H2O System. J. Phys. Chem. Ref. Data. 2018.

(3) Kadam, S. S.; Kramer, H. J. M.; Ter Horst, J. H. Combination of a Single Primary Nucleation Event and Secondary Nucleation in Crystallization Processes. Cryst. Growth Des. 2011.