Entrainment, preferential resolution

Resolution by entrainment can sometimes be used to separate racemic mixtures when there are distinct differences in the rates of crystallization of the two optical isomers. This preferential crystallization is initiated by seeding with the crystals of one enantiomer. This technique has been shown to be effective in the production of thiamphenicol (21). 

Another important but non-synthetic method involves harvesting crops of enan-tioenriched crystals by seeding a supersaturated racemate and is known as resolution by entrainment, or preferential crystallization. These approaches have been well reviewed and will not be covered here [8]. Rare (but spectacular) examples where crystallizations of conglomerates are observed combined with racemization events in solution, leading to total spontaneous resolutions [9], are briefly mentioned in Chapter 7 as there have been interesting recent developments on that front. Included therein are special cases where diastereomeric interactions in solution combined with racemization may yield more than a 50% yield of one enantiomer. 

Preferential crystallization (or resolution by entrainment)—stereospecihc growth of each isomer in two different crystallizers from solution. This process requires no resolving agent. 

Another form of a direct crystallization is a preferential crystallization, which is also called resolution by entrainment of one enantiomer. The process involves solution formation, e.g., under elevated temperature that will then be subcooled and seeded with crystals of the preferred species. Preferential crystallization is a potent method for the improvement of the product quality and at the same time achievement of a higher yield and productivity. For example, by preferential crystallization of DL-threonine from the aqueous solution, it is possible already during a simple batch to gain highly pure enantiomers up to a certain point after which the opposite enantiomer nucleates from the solution and leads to a purity drop. If (—)-hydrobenzoin seed crystals are added to an ethanol solution of ( )-hydrobenzoin, the ( )-enantiomer will crystallize out and after 15 cycles, 97% optical purity can be obtained. 

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