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

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 solvent-mediated transformations, which can render the results unreliable. In this work, we present a rapid microfluidic technique for measuring the 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 the metastable and stable phases. To gain further insights into the observed nucleation behavior, we employed 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.

Crystallization and Polymorphism under Nanoconfinement

“…These include microfluidic devices (MFDs), which have been employed for optimizing protein crystallization and crystal quality, wherein crystallization typically occurs in minute water droplets surrounded by a mobile oil phase. − As an example, a multimicrofluidic crystal generator (MMicroCryGen) device featuring MFD technology is shown in Figure . The emergence of MFDs has prompted their use for polymorphs screening as well, particularly pharmaceutical compounds. ,,,, MFDs permit generation of uniform droplets that simplifies statistical analysis of nucleation and polymorphism. ,− MFDs enable solubility determination (of stable and metastable forms) and polymorph screening directly from powder, saving valuable material crucial during early stage development. − Furthermore, droplet-based methods using MFDs can allow access to unstable and metastable polymorphs through confinement in small volumes. Recently, an automated robotics approach based on crystallization in nanosized droplets encapsulated within an inert oil to regulate solvent evaporation was performed in crystallization trays, allowing for hundreds of parallel experiments and the discovery of a new 13th form of ROY …”