(766b) Optimization of the Bottom-up Precipitation of Nano-Particles of an Ultra-Fast Crystallizer through the Qualitative Characterization of API-Polymer Interactions

Formulations of poorly soluble drugs, seeking to improve bio-availability by API size reduction into the nano-range, typically rely on top-down comminution techniques, e.g. media-milling. While effective, media-milling is costly, time and energy-intensive as well as presenting some isolation challenges. Alternative methods, aiming to access the nano-range through control of the precipitation process, usually rely on very high-intensity mixing in specialty devices like impinging jets and multi-inlet vortex mixers.

For a special class of compounds, crystal nucleation and growth are so fast that even very rapid solvent-antisolvent mixing is insufficient to limit the final crystal size to the nano range.

This work explores the use of polymeric additives to quench the crystal growth of a very fast crystallizer in an attempt at bottom-up nano-crystal precipitation. Lack of first principles understanding of the exact process, through which polymers suppress crystal growth typically leads to high-throughput screening methods for the identification of the optimal additive. However, the large number of potential polymeric candidates, coupled with the parameters controlling the complex high-shear precipitation process lead to a design space too large to explore through brute-force techniques.

Instead, chemometric analysis of the API-polymer interactions was correlated to the performance during precipitation, decoupling polymer optimization from the precipitation process. Identification of specific functional group interactions between the polymer and API also sheds some light on the nature of the crystal growth suppression effect. The combination of high-shear solvent-antisolvent mixing in a rotor-stator wet-mill and polymer additive effect enabled the scalable bottom-up production of nano-particles.