Single Chirality Through Crystal Attrition
PDF Print E-mail

It is important to understand the effect that both enantiomers have on the patient and to produce racemically pure APIs.  This is a difficult task as the right- and left-handed molecules have the same physical properties.  There are various routes available to produce enantiopure material such as asymmetric synthesis, enzymatic resolution, inclusion resolution, diasteriometric salt formation, or chromatographic resolution.  These techniques, however, usually do not yield 100% enantiopure compound.

Crystal attrition experiments in slurries can bring the yield up to 100% as demonstated with sodium chlorate1 and later for organic molecules2.  This method requires the compound to crystallize into a conglomerate crystal system where crystals contain either only right- or left-handed molecules.  To achieve this the compound needs to be racemise in solution which can be delivered using racemization reactions.  The Ostwald ripening process is then used and accelerated by means of attrition to obtain exclusively crystals with a single chirality thereby achieving a 100% enantiopure product.


The major limitation of this technique is the requirement of the system to crystallize into a conglomerate system and only approximately 10% of racemic compounds do so.  The remaining 90% of racemic compounds crystallize into racemate systems, containing both right- and left-handed molecules in the same crystal.  To solve this problem a salt screen or co-crystal screen can provide a co-former or salt former that crystallizes with the compound to produce the required conglomerate system3.

References:
[1] Viedma, C.
2005. Chiral Symmetry Breaking during Crystallization: complete chiral purity induced by nonlinear autocatalysis and recycling. Phys. Rev Letters, 94, 065504
[2] Noorduin, W.L. et al.
J. Am. Chem. Soc. 2008, 130 (4), 1158-1159
[3] Spix, L. et al. Formation of a sant enables complete deracemization of a racemic compound through Viedma ripening,
Cryst. Growth Des. 2014, 14, 1744-1748.