Liquid–Liquid Phase Separation in Highly Supersaturated Aqueous Solutions of Poorly Water-Soluble Drugs: Implications for Solubility Enhancing Formulations

TLDR

Highly supersaturated aqueous drug solutions, common in drug testing and delivery, exhibit complex phase behavior with poorly understood colloidal aggregate formation. The study examined the phase behavior of eight hydrophobic poorly water‑soluble drugs in highly supersaturated aqueous solutions and explained colloid formation via liquid–liquid phase separation. Using temperature‑dependent phase diagrams, especially for the ritonavir–water system, the authors showed that LLPS occurs in the metastable region and precedes crystallization. They found that the LLPS onset concentration correlates with the predicted amorphous solubility, that supersaturation is limited by the LLPS transition concentration in an amorphous solid dispersion, and that these approaches enable assessment of supersaturating systems and determination of amorphous solubility.

Abstract

Highly supersaturated aqueous drug solutions are often generated during drug testing and upon delivery to the patient. The phase behavior of such solutions appears complex and poorly understood, with the formation of colloidal drug aggregates often being reported. In this study, the phase behavior of eight hydrophobic poorly water-soluble drug molecules in highly supersaturated aqueous solutions was examined, and colloid formation was explained in terms of liquid–liquid phase separation (LLPS). A relationship was found between the concentration at which LLPS was observed and the theoretically predicted amorphous "solubility" value, where the latter was predicted based on the thermodynamic properties of the crystalline solid/supercooled liquid and solution activity coefficients. A phase diagram for the ritonavir–water system as a function of temperature was used to demonstrate that LLPS occurs in the metastable region of the phase diagram, and thus LLPS is a precursor to crystallization. Using an amorphous solid dispersion of ritonavir and poly(vinylpyrrolidone), it was shown that there is an upper limit to the extent of supersaturation achievable by a supersaturating dosage form and that this limit is dictated by the LLPS phase transition concentration. The approaches outlined in this study provide an alternative way to assess the properties of supersaturating systems, including the determination of the amorphous solubility.