Mapping Nucleation and Growth Kinetics of Pharmaceutical Solutes Using Data-Rich Kinetic Screening

Separation via crystallization is one of the most important steps in producing lifesaving medications in the pharmaceutical industry. Crystallization is one of the most popular separation processes in pharmaceutical manufacturing, yet there is a lack of fundamental understanding of how to design these processes with limited amounts of time and material. Crystallization kinetics play a critical role in gaining the required understanding needed for crystallization process development. However, there is no standard method to screen for kinetics, which depend highly on variables like scale, impurities, or techniques for measuring crystal growth. Each new compound requires a specifically and uniquely designed process, which becomes time and material intensive.

In a recent publication, we described a set of automated methods for the rapid screening of nucleation and growth kinetics, requiring one week and material at the 1-10 g scale. These methods were found to be consistent across multiple operators, instruments, and sites. By implementing that framework over multiple different systems, we’ve now created a database including nucleation and growth constants for common pharmaceuticals, all collected in consistent conditions of scale, mixing, and temperature, and decoupling the effect of supersaturation using population balances.

The database allows for the prediction of crystal behaviors based on the similarity to other previously studied systems when subjected to consistent methods. Process development scientists will be able to screen an entirely unknown compound as fast as one week and begin process development earlier. The presented methods will serve as the standardized workflow for crystallization process development, which will aid scientists in the design of their processes based on leveraging the behavior of already well-characterized systems.