Deracemization and Real Time Raman Spectroscopy

Deracemization processes are of high interest for the pharmaceutical industry as pharmaceutical products often must be registered in enantiomerically pure form. On the same line, in the agrochemical industry, in case a chiral product is more active in one of the enantiomeric forms, an enantiomerically pure form can reduce the amount of pesticides needed for crop protection. Therefore, crystallization offers an attractive method for separation of chiral molecules.

Deracemization processes such as temperature cycling (1) and Viedma ripening (2) are more and more used and applied at larger scales. These methods are typically carried out at lab scale batch mixed with crystallizer vessels, where grinding or heat-cool cycles ensure the complete transformation into a homochiral phase. There are several examples of successful deracemization processes of chiral active pharmaceutical ingredients and intermediates. (3-9).

Nevertheless, besides the need of crystallizing one enantiomerically pure form, there is also a high demand in adequate, easily accessible analytical technology that can monitor these critical processes. Xiouras et al have successfully used in situ Raman spectroscopy to monitor the complicated deracemization process of NCPA (10-11). Raman spectroscopy is known to be a chiral blind method when compared to other analytic tools. Nevertheless, by making use of Raman spectroscopy, one can detect specific lattice vibrations for the different crystal structures. Therefore, Raman can be used to distinguish between those enantiomers that are packed in different crystal structures. 

The CrystallineRR gives the user access to real time Raman spectroscopy, in combination with a sophisticated parallel crystallizer where seeding the right enantiomer has never been easier. With the CrystallineRR, it is easy to follow crystallization processes and to study polymorph conversions, hydration or the formation of solvates in slurries. On the Crystalline instrument, the temperature cycling method can be easily implemented and the deracemization process followed with real time Raman spectroscopy in those cases the enantiomers are packed in different crystal structures.  While one is performing the crystallization experiment, seeding can be easily performed and followed. 

Do you want to know more about deracemization? Check our webinar on this topic:

Viedma Ripening and Temperature Cycling: Two Robust Deracemization Methods




Do you want to know more about solubility? Check our webinar on this topic:

Crystal Solubility: Importance, Measurement and More




(1) Suwannasang, K.; Flood, A. E.; Rougeot, C.; Coquerel, G. Using programmed heating-cooling cycles with racemization in solution for complete symmetry breaking of a conglomerate forming system. Cryst. Growth Des. 2013, 13, 3498−3504.
(2) Viedma, C. Chiral symmetry breaking during crystallization: Complete chiral purity induced by nonlinear autocatalysis and recycling. Phys. Rev. Lett. 2005, 94,3−6. 
(3) Viedma, C.; Ortiz, J. E.; De Torres, T.; Izumi, T.; Blackmond, D. G. Evolution of Solid Phase Homochirality for a Proteinogenic Amino Acid Evolution of Solid Phase Homochirality for a Proteinogenic Amino Acid. J. Am. Chem. Soc. 2008, 130, 15274−15275. 
(4) Spix,L.;Meekes,H.;Blaauw,R.H.;VanEnckevort,W.J.P.;Vlieg, E. Complete deracemization of proteinogenic glutamic acid using viedma ripening on a metastable conglomerate. Cryst. Growth Des. 2012, 12, 5796−5799. 
(5) Wilmink, P.; Rougeot, C.; Wurst, K.; Sanselme, M.; Van Der Meijden, M.; Saletra, W.; Coquerel, G.; Kellogg, R. M. Attrition inducedderacemisationof2-fluorophenylglycine.Org.ProcessRes.Dev. 2015, 19, 302−308. 
(6) Kaptein, B.; Noorduin, W. L.; Meekes, H.; Van Enckevort, W. J. P.; Kellogg, R. M.; Vlieg, E. Attrition-enhanced deracemization of an amino acid derivative that forms an epitaxial racemic conglomerate. Angew. Chem., Int. Ed. 2008, 47, 7226−7229. 
(7) Kawasaki, T.; Takamatsu, N.; Aiba, S.; Tokunaga, Y. Spontaneous formation and amplification of an enantioenriched αamino nitrile: A chiral precursor for Strecker amino acid synthesis. Chem. Commun. 2015, 51, 14377−14380. 
(8) Kellogg, R.; Van der Meijden, M.; Leeman, M.; Gelens, E.; Noorduin, W.; Meekes, H.; Van Enckevort, W.; Kaptein, B.; Vlieg, E. Attrition-Enhanced Deracemization in the Synthesis of Clopidogrel-A Practical Application of a New Discovery. Org. Process Res. Dev. 2009, 13, 1195−1198. 
(9) Noorduin, W. L.; Kaptein, B.; Meekes, H.; Van Enckevort, W. J. P.; Kellogg, R. M.; Vlieg, E. Fast attrition-enhanced deracemization of naproxen by a gradual in situ feed. Angew. Chem., Int. Ed. 2009, 48, 4581−4583.
(10) Christos Xiouras, Giuseppe Belletti, Raghunath Venkatramanan, Alison Nordon, Hugo Meekes, Elias Vlieg, Georgios D. Stefanidis, and Joop H. Ter HorstCryst. Toward Continuous Deracemization via Racemic Crystal Transformation Monitored by in Situ Raman Spectroscopy. Growth Des. 2019, 19, 5858−5868.
(11) McBride, J. M.; Tully, J. C. Did life grind to a start? Nature 2008, 452, 161−162.