Metastable intermediate phases on molecular crystallisation pathways

Pharmaceutical industry has significant interest in developing well controlled crystallization and precipitation processes for producing crystalline particulates with desired polymorphism, morphology and particle size distribution in order to optimise further post-processing and formulation steps. While it is empirically well known that mixing and flow conditions have strong effect on crystal nucleation processes, understanding and controlling these remains an open challenge in terms of fundamental science as well as industrial applications.

We have experimentally studied nucleation of amino acids (glycine, valine) and small pharmaceutical molecules (aspirin, carbamazepine) from aqueous and mixed solvent systems in both cooling and antisolvent crystallisation. We have used both batch and continuous mixers to provide controlled and reproducible mixing conditions with a wide range of mixing times, since changing the initial mixing conditions leads to dramatic effects on nucleation kinetics as well as on resulting particle size distributions. Undersaturated and supersaturated solutions were characterised with a range of spectroscopic and scattering techniques, including NMR, IR, spectrophotometry, small angle static and dynamic light scattering, and small angle x-ray scattering in order to monitor both liquid phase processes and formation of solid phase particulates.

In the systems studied it was typically observed that there were two populations of liquid phase precursors: molecular clusters with sizes up to a couple of nanometres and larger mesoscopic domains of submicron dimensions. Size distribution of these domains was dependent on supersaturation as well as mixing conditions involved, and it was also correlated with resulting crystal induction times and resulting crystal size distributions. We propose that the observed domains present metastable intermediate liquid-like phases on molecular crystallisation pathways.