Attrition-Enhanced Deracemization of NaClO 3 : Comparison between Ultrasonic and Abrasive Grinding

Self Cite

It has been recently observed that coupling Viedma ripening with a seeded in-situ metastable racemic crystal to conglomerate transformation leads to accelerated and complete deracemization: crystal transformation-enhanced deracemization. By means of a simple kinetic model, we show that the mechanistic pathway of this new process depends profoundly on the interplay between the crystal transformation and racemization processes, which in turn influence the nucleation process of the counter enantiomer. If the nucleation of the counter enantiomer is suppressed (e.g. by sufficiently fast racemization, low amount of racemic compound or gradual feed, low relative solubility between racemic compound and conglomerate), deracemization proceeds via a second order asymmetric transformation (SOAT) and is limited primarily by the dissolution rate of the racemic crystals and the growth rate of the preferred enantiomer crystals. Breakage and agglomeration accelerate the process, but contrary to conventional Viedma ripening, they are not essential ingredients to explain the observed enantiomeric enrichment. If the nucleation process of the counter enantiomer is not sufficiently suppressed, deracemization is initially controlled by the dissolution rate of the racemic crystals, but Viedma ripening is subsequently required to convert the conglomerate crystals of the counter enantiomer formed by nucleation, resulting in slower deracemization kinetics. In both cases, the combined process leads to faster deracemization kinetics compared to conventional Viedma ripening, while it autocorrects for the main disadvantage of SOAT, i.e. the accidental nucleation of the counter enantiomer. In addition, crystal transformation-enhanced deracemization extends the range of applicability of solid-state deracemization processes to compounds that form metastable racemic crystals. interplay between the crystal transformation and racemization processes, which in turn influence the nucleation process of the counter enantiomer. If the nucleation of the counter enantiomer is 3 suppressed (e.g. by sufficiently fast racemization, low amount of racemic compound or gradual feed, low relative solubility between racemic compound and conglomerate), deracemization proceeds via a second order asymmetric transformation (SOAT) and is limited primarily by the dissolution rate of the racemic crystals and the growth rate of the preferred enantiomer crystals.Breakage and agglomeration accelerate the process, but contrary to conventional Viedma ripening, they are not essential ingredients to explain the observed enantiomeric enrichment. If the nucleation process of the counter enantiomer is not sufficiently suppressed, deracemization is initially controlled by the dissolution rate of the racemic crystals, but Viedma ripening is subsequently required to convert the conglomerate crystals of the counter enantiomer formed by nucleation, resulting in slower deracemization kinetics. In both cases, the combined process leads to faster deracemization kinetics compared ...

Section: Introductionmentioning

confidence: 99%

Coupling Viedma Ripening with Racemic Crystal Transformations: Mechanism of Deracemization

Xiouras

Horst

Gerven

et al. 2017

Self Cite

“…The enantiomeric excess E of the solids was determined using a similar procedure as reported elsewhere. 25 A sample of the slurry was taken from the crystallizer using a disposable serological pipette. Three large drops were pipetted on a petri dish which was subsequently covered with filtration paper to prevent contamination of dust particles and to reduce the rate of solvent evaporation.…”

Section: Process Analysismentioning

confidence: 99%

“…The use of ultrasound was furthermore effective in the batch deracemization approach of sodium chlorate through Viedma ripening. 25 Therefore, the use of ultrasound could be an interesting avenue of research to achieve efficient Continuous Total Spontaneous Resolution experiments in which fouling would be suppressed and the unseeded chiral form would be transformed into the seeded form through Viedma ripening. In our experiments, the effect of fouling of counter chirality crystals could be suppressed to some extent.…”

Section: Enhancing Secondary Nucleationmentioning

confidence: 99%

Continuous Total Spontaneous Resolution

Steendam

Horst

2017

Self Cite

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.

“…[21][22][23][24] The focal points of studies on Viedma ripening were often placed on mechanistic aspects 12,14,25 , on widening the scope of its application (new classes of compounds 26 , metastable solid phases 27 , etc. ), as well as exploring different operating modes (involving grinding [28][29][30] , sonication 31 , temperature cycling 32,33 or combinations thereof).…”

Section: Introductionmentioning

confidence: 99%

Design and Performance Assessment of Continuous Crystallization Processes Resolving Racemic Conglomerates

Köllges

Vetter

2018

Continuous crystallization processes achieving the complete resolution of racemic feed mixtures of conglomerate forming substances are presented. The processes considered rely on the principles of preferential crystallization or attrition-enhanced deracemization (Viedma ripening). A single mechanistic population balance model is shown to describe both operating modes. For the case of isothermal Viedma ripening, a shortcut method is introduced that allows the rapid and computationally efficient design of processes using a single or multiple ripening stages. The achievable productivity and enantiomeric purity are determined for all process variants in a wide range of operating conditions and Pareto optimal operating points are identified. Since our results are obtained with a consistent set of kinetics for all operating modes, an unbiased comparison is enabled. It is shown that the productivity of the ripening process can be improved by using cascades of multiple crystallizers, but that the preferential crystallization process still achieves higher productivity at full enantiomeric purity.