Liquid Metastable Precursors of Ibuprofen as Aqueous Nucleation Intermediates

Abstract

The nucleation mechanism of crystals of small organic molecules, postulated based on computer simulations, still lacks experimental evidence. In this study we designed an experimental approach to monitor the early stages of the crystallization of ibuprofen as pharmaceutically eminent molecule and a model system for small organic molecules. We found that ibuprofen undergoes liquid-liquid phase separation prior to nucleation. The binodal and spinodal limits of the corresponding liquid-liquid miscibility gap were localized by combining potentiometric titration with 1 H NMR spectroscopy and additional analyses. We confirmed the liquid character of this initially formed phase by applying PFG-STE self-diffusion experiments ( 1 H NMR) and found an increase in viscosity sustaining the kinetic stability of the dense liquid intermediate. Intermolecular distances of ibuprofen within the dense liquid phase were found to be similar to those in the crystal forms, according to 2D 1 H- 1 H NOESY measurements. Hence, this dense liquid phase is identified as a precursor phase within a nucleation pathway of ibuprofen, in which densification is followed by structural order generation. Fundamentally, this discovery bears the opportunity and promise to enrich poorly soluble pharmaceuticals beyond classical solubility limitations in aqueous environments.