Automated and Material-Sparing Workflow for the Measurement of Crystal Nucleation and Growth Kinetics

The development of digital twins for model-based crystallization process development is often limited by the associated material-intensive and time-intensive experimental screenings. Methods for measuring primary nucleation rates are well established and common practices for academic studies; however, methods for the measurement of secondary nucleation and crystal growth rates are often inconsistent due to differing strategies in the selection of supersaturation models, particle size measurement techniques, and investigated scales. We hereby provide a workflow of automated methods for the experimental screening, data analysis, and parameter estimation for secondary nucleation and crystal growth kinetics in solution crystallization. The methods have been integrated with common experimental protocols in the determination of induction times for primary nucleation and with the use of commercially available tools that can be found in crystallization laboratories across academia and industry. These tools include a Technobis Crystalline as well as process simulation software, currently tailored to gPROMS FormulatedProducts. The methods have been demonstrated for two well-known model systems: antisolvent crystallization of acetaminophen from ethanol-water mixtures and cooling crystallization of a metastable polymorph of l-glutamic acid from water. The presented workflow will serve as a basis to standardize the analysis of crystallization kinetics for new systems, generating kinetic trends using similar methods that would aid in early process development as well as in academic studies.