Particle tuning in reactive crystallization via microwave-assisted temperature cycling for improved downstream performance

Abstract

Efficient particle processing during and downstream of a crystallization process is a paramount task in pharmaceutical industry regarding production of Active Pharmaceutical Ingredients (APIs). Due to mass transfer limitations, supersaturation is often not uniformly controlled in reactive crystallization processes generating an excessive amount of fine particles, which often tend to agglomerate causing issues in downstream operations, such as filtration and drying. We demonstrate rapid microwave-assisted temperature cycling (RMWTC) as a post-treatment approach that can effectively address these problems. Specifically, we report that in the event of high solids load systems, RMWTC intensifies fines dissolution during rapid heating and promotes faster recrystallization on surviving surfaces during rapid cooling. The RMWTC approach facilitates tuning not only of particle size, but possibly of crystal morphology by increasing the number of stable agglomerates with a positive concomitant impact on particle filterability and process time. A thermal parametric study on an aromatic amine API intermediate system revealed that there is an optimal temperature operating window (60 °C-105 °C) that shifts particle size distribution (PSD) towards larger particle sizes and yields up to 82 % improved filterability at 50 % less process time compared to the traditional particle control strategy, currently applied in industry for this process.