On the Effect of Secondary Nucleation on Deracemization through Temperature Cycles

Abstract

Herein, the pivotal role of secondaryn ucleation in ac rystallization-enhanced deracemization process is reported. During this process, complete and rapid deracemization of chiral conglomerate crystalso fa ni soindolinone is attained through fast microwave-assistedt emperature cycling. Ap arametric study of the main factorst hat affect the occurrence of secondary nucleation in this process, namely agitation rate, suspension density,a nd solutes upersaturation, confirmst hat an enhanced stereoselective secondary nucleation rate maximizest he deracemizationr ate. Analysis of the systemd uring as ingle temperature cycle showed that, although stereoselective particlep roduction during the crystallization stage leadstoenantiomeric enrichment, undesired kinetic dissolution of smaller particleso ft he preferred enantiomero ccurs during the dissolution step. Therefore, secondary nucleationi sc rucial for the enhancemento fd eracemization through temperature cycles and as such should be considered in further design and optimization of this process, as well as in other temperature cyclingp rocesses commonly applied in particle engineering.

Deracemization via Periodic and Non-periodic Temperature Cycles: Rationalization and Experimental Validation of a Simplified Process Design Approach

“…A few researchers found that the process is faster when a larger fraction of the solid amount is dissolved per temperature cycle. 11,16,19,20 This is expected because in this case, the distomer amount that can convert is larger, but it is also surprising considering that a larger amount of the eutomer can dissolve as well.…”

“…Different works focused on the effect of such operating conditions on the process performance in order to master the design of highly productive operations. − Among the parameters investigated, we find notably the initial enantiomeric excess and the temperature range and also the amplitude of the temperature cycle and the initial suspension density, which contribute to determine the amount of solid that can dissolve, and thus potentially deracemize, in each temperature cycle. A few researchers found that the process is faster when a larger fraction of the solid amount is dissolved per temperature cycle. ,,, This is expected because in this case, the distomer amount that can convert is larger, but it is also surprising considering that a larger amount of the eutomer can dissolve as well.…”

Punin Ripening and the Classification of Solution-Mediated Recrystallization Mechanisms

“…As first implemented, a racemic population of NaClO 3 crystals was deracemized by abrasive grinding of saturated aqueous slurries. Even slurries of very small enantiomeric excesses ( ee ) convert to slurries with crystals of only one enantiomorph on the laboratory time scale. − While VR can occur in stagnant slurries, the process is accelerated by energy inputs such as ultrasound, stirring with glass beads (attrition), , boiling (temperature gradients), − or temperature oscillations. − VR also can be accelerated by crystal aggregation, the enantioselective capture of subcritical crystallites, rescuing them from dissolution. ,− The crystal sizes typically range from tens to hundreds of microns, but this mechanism can be efficient for larger crystals too.…”

Crystallization-Induced Deracemization: Experiments and Modeling

“…Among these processes, 1 − 8 deracemization via temperature cycles has been the focus of experimental and modeling studies carried out by various research groups with the aim of identifying the relevant operating parameters and simplifying the process design. 5 , 9 − 20 In our recent work, 21 we identified a design parameter, i.e. the dissolution factor, demonstrated its primary role, and showed that high productivity values are attained for small values of the dissolution factor.…”