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

Abstract

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.

Exploration of the polymorphic solid-state landscape of an amide-linked organic cage using computation and automation

“…Low-cost computational modelling was used to identify five stable conformers of dynamic cage 1 (250 atoms). These discrete conformers were then realised in different polymorphs using a high-throughput crystallisation workflow using a commercial liquid handling robot that allows for standardisation, reproducibility 46,48 and the generation of FAIR datasets over vast chemical space that facilitate future data science and machine learning efforts. 49 Our setup can be transferred to molecular crystals where solvent composition may affect crystal formation or the complexity of the observed structures goes beyond state-of-the-art crystal structure prediction.…”

Opencrystaldata: An Open-Access Particle Image Database to Facilitate Learning, Experimentation, and Development of Image Analysis Models for Crystallization Processes

“…Crystallization process has applications in pharmaceutical, food, and chemical industries where it is used to produce crystals with desired properties, such as purity, shape, and crystal size distribution (CSD). (Arruda et al, 2023;McGinty et al, 2020) Among different process analytical technology (PAT) tools, image-based PATs have recently gained popularity in facilitating rapid crystallization process design, and process monitoring and control. The growing interest in using these tools is mainly because of their ability to function as an information-gathering tool, supporting process understanding and robustness assessment.…”

Rapid Assessment of Crystal Nucleation and Growth Kinetics: Comparison of Seeded and Unseeded Experiments

“…Systematic workflow approaches to crystallization process development and characterization have been presented in recent literature ,, based on a rapid experimental screening using widely available crystallization platforms. These approaches use small-scale experiments to provide data on crystallization kinetics under a wide range of experimental conditions.…”

“…However, this is often related to sensitivity limits of experimental methods used, and care must be taken when interpreting and presenting such results. For example, isothermal induction time experiments can be conveniently conducted at timescales from minutes to hours or days, which requires a characteristic time of nucleation 1/JV on the comparable timescales, so that only up to three orders of magnitudes of absolute values of primary nucleation rates J are practically accessible at a given volume scale V. Systematic workflow approaches to crystallization process development and characterization have been presented in recent literature 7,13,14 based on a rapid experimental screening using widely available crystallization platforms. These approaches use small-scale experiments to provide data on crystallization kinetics under a wide range of experimental conditions.…”