Continuous total spontaneous resolution

Steendam, René R.E. and Ter Horst, Joop H. (2017) Continuous total spontaneous resolution. Crystal Growth and Design, 17 (8). pp. 4428-4436. ISSN 1528-7483 (

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We achieved chiral symmetry breaking through continuous crystallizations, which enables the continuous industrial production of chirally pure crystals. For this, a novel recycling platform that mimics a continuous cooling crystallization process with a hot concentrated feed and an outflow of cold suspension was developed and tested. A virtually enantiopure steady-state was realized by seeding a clear supersaturated achiral solution with enantiopure seed crystals at the start of the experiment. Seeding with the enantiopure form ensured that fragments of the seeded form were continuously created through secondary nucleation. Below the metastable zone limit, the product continued to consist of crystals of the same handedness as the seeded form provided that long residence times were applied in combination with sufficiently high feed concentrations. Short residence times in combination with low feed concentrations led to fouling-induced formation of both chiral forms and a decrease in the product's enantiomeric excess. Overall these results demonstrate the feasibility of continuous total spontaneous resolution of chiral pharmaceutical products in an industrial setting. This continuous manufacturing approach provides many benefits including ease of operation, consistent product quality, and a high degree of process control.