Direct-inject liquid-chromatography enables an autonomous continuous preferential crystallization platform

Abstract

Access to both enantiomers of chiral building blocks remains a fundamental challenge in chemical synthesis, particularly for scalable applications in pharmaceuticals, agrochemicals, and materials development. Continuous preferential crystallization (CPC) offers a promising route to obtain enantiomerically enriched compounds from racemic mixtures without the use of chiral auxiliaries. However, its widespread adoption is hindered by the need for precise supersaturation control mediated by real-time process analytical technologies capable of monitoring enantiomeric ratio. Here, we report the development of an autonomous CPC platform enabled by online chiral high-performance liquid chromatography. Using our Direct Inject Liquid Chromatography (DILC) module, we continuously monitor the crystallization process and implement feedback control that initiates temperature-based dissolution in response to early detection of undesired enantiomer accumulation. The trigger threshold is set from the measured noise in the baseline signal, so the controller responds to signal breakthrough rather than the scatter in the measurement, allowing it to run for days without supervision. Applied to the CPC of allylalanine monohydrate, a conglomerate-forming α-amino acid, this system achieved multi-day operation and gram-scale production of enantiopure material with minimal supervision. The platform establishes a generalizable strategy for real-time control of enantioselective crystallizations and opens new avenues for self-driving purification technologies.