Amelia Bellman

Liquid-liquid extractions are commonly used across chemical process development to remove any undesired components including solvents, impurities, and catalysts from a reaction. Traditionally, these extractions are performed on a large scale and are therefore, low throughput, labour intensive, and time consuming. High-throughput techniques have been increasingly applied to accelerate chemical process development, executing many reactions across a wide design space and generating large data sets in a shorter period of time. This includes crystallisations and reaction optimisations, but less has been done regarding high-throughput reaction workup, as this workflow requires the implementation of state-of-the-art robotic platforms and the set-up of complex data management systems to collate information from different analytical techniques to a central repository.

Herein, we outline the automated liquid-liquid extraction workflow that has been developed for immiscible organic and aqueous phases as part of the high throughput strategy in Chemical Development at GSK. The use of the Unchained Labs’ Freeslate CM3 platform is demonstrated. This workflow includes an automated image analysis script for determining phase volumes, combining images taken on the Freeslate platform with a fit-for-purpose MATLAB^TM code. One of the main elements of the workflow is the automated and individual sampling of the organic and aqueous phase from the same sample (sampling from different heights) to obtain accurate density measurements for each one.

In addition to the controlled sampling, several process parameters such as mixing rate and time, concentrations and pH, are systematically investigated to maximise the yield/purity of the desired product.

A 30-second high-throughput UPLC method was applied, along with KF and NMR to understand API recovery, partitioning of all reaction components and obtain a full mass balance. in partnership with Metrohm, an industry-first high-throughput KF instrument, capable of handling plates in a fully automated workflow, was developed. Furthermore, the application of a 13-component test mix to the UPLC is discussed, helping to detect and troubleshoot faults with the instrument.

The workflow demonstrates the importance of high-throughput technologies and their applicability in chemical process development in lieu of traditional manual methods, allowing this to be continually applied to projects in Chemical Development.