Microfluidics Platform for Polymorph Screening Directly from Powder

Abstract

We describe a microfluidic platform for solid phase screening using extremely small quantities of raw materials. Based on our previous set-up for solubility measurement that generates saturated solutions directly from powder, the platform requires no solution in excess of that used for the dropletcrystallization experiment. The set-up is compatible with most solvents and molecules without using surfactant. Using this microfluidic platform, we first measured the solubility of Sulfathiazole in water, isopropanol, and acetonitrile. Second, we performed a polymorph screening of Sulfathiazole using as little as 30 mg of raw material, for numerous identical cooling crystallization experiments from 80 to 10°C. In the experiments presented, we obtained the 3 usual polymorphs of Sulfathiazole. We show that this economical approach yields reliable information on the probability of nucleation of a given polymorph, useful in pharmaceutical development.

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 …”

Advances in protein solubility and thermodynamics: quantification, instrumentation, and perspectives

“…In addition, lyophilized protein contains additional components such as water and salt, which can significantly impact solubility measurement. 73,74…”