Crystallisation processes have evolved to practical methods that allow isolation of an enantiopure product in high yield. Viedma ripening in particular enables access to enantiopure products in a reliable way, simply through grinding of crystals in a solution. This tutorial review covers the basic principles behind asymmetric crystallisation processes, with an emphasis on Viedma ripening, and shows that to date many novel organic molecules can be obtained in enantiopure solid form.

The synthesis of enantiopure molecules from achiral precursors without the need for pre-existing chirality is a major challenge associated with the origin of life. We here show that an enantiopure product can be obtained from achiral starting materials in a single organic reaction. An essential characteristic of this reaction is that the chiral product precipitates from the solution, introducing a crystal–solution interface which functions as an asymmetric autocatalytic system that provides sufficient chiral amplification to reach an enantiopure end state. This approach not only provides more insight into the origin of life but also offers a pathway to acquire enantiopure compounds for industrial applications.

Insight into nucleation kinetics and other nucleation parameters can be obtained from probability distributions of induction time measurements in combination with the classical nucleation theory. In this work, induction times of crystallization were recorded using a robust and automated methodology involving a focused beam reflectance measurement probe. This methodology is easily interchangeable between different crystallizers which allowed us to investigate the effects of scale-up on the kinetics of crystal nucleation of paracetamol from 2-propanol in four different crystallizers, ranging from small magnetically stirred 10 mL solutions to overhead-stirred solutions of 680 mL. The nucleation rate was an order of magnitude faster in the magnetically stirred crystallizer as compared to the crystallizers involving overhead stirring. The thermodynamic part of the nucleation rate expression did not significantly change the nucleation rate, whereas the kinetic nucleation parameter was found to be the rate-determining process when the crystallization process was scaled-up. In particular, the shear rate was rationalized to be the part of the kinetic parameter that changes most significantly when the crystallization process was scaled-up. The effect of shear rate on the nucleation kinetics decreases with increasing volume and plateaus when the volume becomes too large. In this work, the nucleation mechanism was also investigated using the chiral sodium chlorate system. These experiments showed that the single nucleus mechanism is the underlying nucleation mechanism in all four tested crystallization setups when supersaturation remains the same. When the supersaturation was changed continuously through cooling, crystallization was driven by a multinucleus mechanism. The automated and robust method used to measure induction times can easily be extended to other crystallizers, enabling the measurement of induction times beyond small crystallizer volumes.

Viedma ripening proceeds through an autocatalytic feedback mechanism which exponentially deracemizes an initially racemic solid state to an enantiopure end state. Here we show that, in the presence of enantiopure additives with a concentration of as low as 2.5 × 10 −2 mol %, Viedma ripening proceeds with an overall linear and faster increase in enantiomeric excess. These experimental results can be explained using a simple model which assumes a difference in growth and dissolution rates between the enantiomers. This model also accounts for the generally observed linearity during the initial stages of Viedma ripening without additives.

Spontaneous symmetry breaking and chiral amplification by means of Viedma ripening by definition should result in complete deracemization of a racemic conglomerate into either one of the enantiomers with equal probability. In practice, however, chiral impurities influence Viedma ripening and one enantiomer is obtained in preference over the other. Here, we show that by increasing the attrition intensity during Viedma ripening, the effect of chiral impurities is suppressed and deracemization does yield either enantiomer with equal probability. The reason for this is that the resulting smaller crystals lead to such a low surface density of chiral impurities that they no longer inhibit the crystal growth sufficiently to determine the chiral outcome. Furthermore, we show that even for low attrition intensities, the effect of chiral impurities can be canceled by using the right amount (10 ppm) of chiral additives.

Here we demonstrate that deracemization of isoindolinones using Viedma ripening is possible starting from a racemic mixture of conglomerate crystals. Crystals of the enantiopure isoindolinones lose their chiral identity upon dissolution even without the need for a catalyst. This enabled complete deracemization of the reported isoindolinones without a catalyst.

The total synthesis of (±)-janoxepin, a novel antiplasmodial d-leucine derived oxepine-pyrimidinone-ketopiperazine isolated from the fungus Aspergillus janus, is described. The cornerstones of the synthetic route are pyrimidinone preparation, ring-closing metathesis, aldol introduction of the enamide, and dihydro-oxepine elaboration. This synthetic route proved very efficient for the formation of a number of janoxepin analogues, including dihydro-janoxepin and tetrahydro-janoxepin.

We achieved chiral symmetry breaking through continuous crystallization, 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 2 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.