(116c) Nanodroplet Intermediates On a Molecular Crystallization Pathway

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. Although there has recently been significant progress towards understanding crystallization mechanisms at the molecular level, understanding and controlling nucleation processes still remains an open challenge in terms of fundamental science as well as industrial applications. It is also well known that mixing and flow conditions during various steps of the crystallization process has strong effect on crystal formation and resulting particulate properties of pharmaceutical products.

The rate of crystallization of the amino-acid valine from a mixture of water (solvent) and 2-propanol (antisolvent) was found to depend strongly on the intensity of the mixing used to prepare supersaturated solutions. Spectrophotometry, proton nuclear magnetic resonance and dynamic light scattering, were used to probe the evolution of the system from a transparent solution to a suspension of microcrystals. Combining aqueous valine with 2-propanol at ambient temperature to produce near saturated solutions resulted in formation of an inhomogeneous liquid phase comprising transparent nanodroplets (100-400 nm) dispersed in valine solution. More highly supersaturated solutions prepared by vortexing or rapid magnetic stirring gave rise to larger valine-rich nanodroplets (>700 nm). The average size and size distribution varied with concentration and the type, intensity and period of mixing.

The presence of a large nanodroplets correlated with production of more microcrystals. Formation of supersaturated solutions by cooling, without agitation, produced a narrow distribution of smaller nanodroplets (100-300 nm) and the rate of crystallization was up to 500 times slower, generating only a few large crystals. Finally it was demonstrated that redissolution of valine crystals into under-saturated solution resulted in formation of nanodroplets and that these originated from and coexisted with suspended crystals. The data demonstrate solute-rich nanodroplets exist within a thermodynamically stable phase which becomes metastable only at higher solute concentrations. Coalescence of metastable nanodroplets provides access to an alternate rapid crystallization pathway and this helps to explain why mixing has such a profound effect on crystal nucleation.