Microdroplet Approach for Measuring Aqueous Solubility and Nucleation Kinetics of a Metastable Polymorph: The case of KDP Phase IV

TL;DR

This paper introduces a microfluidic method to accurately measure the solubility and nucleation kinetics of metastable polymorphs, exemplified by KDP Phase IV, revealing thermodynamic and kinetic interplay at high supersaturation levels.

Contribution

The study presents a novel microdroplet technique for measuring metastable phase solubility and interfacial energies, enabling insights into polymorphic nucleation beyond previous limitations.

Findings

Metastable KDP Phase IV solubility measured accurately.

Interfacial energies of metastable and stable phases calculated.

Nucleation behavior aligns with Classical Nucleation Theory predictions.

Abstract

Solubility and interfacial energy are two fundamental parameters underlying the competitive nucleation of polymorphs. However, solubility measurement of metastable phases comes with a risk of solventmediated transformations which can render the results unreliable. In this work, we present a rapid microfluidic technique for measuring aqueous solubility of the metastable form using KDP Phase IV as a model system. This bracketing approach involves analyzing the dissolution behavior of crystals in contact with supersaturated microdroplets generated via evaporation. Then, with the help of our recently developed nucleation time measurement technique, together with Mersmann calculation of interfacial energies from solubilities, we were able to access the interfacial energies of both metastable and stable phases. To gain further insights into the observed nucleation behavior, we employed the Classical Nucleation Theory (CNT) to model the competition of polymorphs using our measured solubility and calculated interfacial energies. The results show that the stable form is favored at lower supersaturation while the metastable form is favored at higher supersaturation, in good agreement with our observations and experimental reports in the literature. Overall, our microfluidic approach allows access to unprecedentedly deep levels of supersaturation and reveals an interesting interplay between thermodynamics and kinetics in polymorphic nucleation. The experimental methods and insights presented herein can be of great interest, notably in the mineral processing and pharmaceutical industry.