Enantiomers resolution phase diagrams

The use of dissociable diastereomers for enantiomer resolution may be illustrated by the case where racemic mandelic acid is resolved using en-antiomerically pure a-methylbenzylamine. The n and p salts of a-methylbenzyl-amine mandelate have aqueous solubilities of 49.1 and 180 g/L, respectively, at 25°C [153], A more recent example, which focuses on the crystallographic origin of the solubility differences, is provided by the resolution of ( )-mandelic acid with (-)-ephedrine in water or methanol solution [154], In general, the relative solubilities of the n and p salt pairs are strongly influenced by the choice of solvent medium and temperature, which provide considerable flexiblity in optimizing the crystallization conditions and the efficiency of resolution. This process may be facilitated by the development of a full solubility phase diagram. 

The attainment of high levels of enantiopurity is not always possible by enzymatic or diaste-reomeric resolutions or by asymmetric syntheses alone. It is however frequently possible to prepare a pure enantiomer from a partially resolved sample by simple recrystallization. For this process to proceed successfully it is necessary that the initial enantiopurity of the mixture is greater than that of the eutectic point in the phase diagram. By utilization of the phase diagram, the optimal quantity of solvent required can be calculated. It is also possible to calculate the maximum expected yield. 

Pseudoracemates may exhibit three types of ternary phase diagram, as mentioned previously (Fig. 6c). The change of solubility with composition is relatively small. Therefore we may expect similar solubilities and intrinsic dissolution rates for the enantiomer and the pseudoracemate. For the same reason, resolution of a pseudoracemate by crystallization is practically impossible [10]. 

Supersaturated racemic solutions are unstable or metastable depending on the degree of supersaturation. For a system having a phase diagram as shown in Figure 3, the initial levels of the driving force for the crystallization are the same to the both enantiomers, i.e. AM for the L-isomer and BM for the D-isomer. Accordin y at the end of the complete crystallization when the true equilibrium is established, i.e. when no resolution results, the saturated solution ( ) and two crystal phases of the enantiomers (L and D) of the equal amounts coexist. There may be no need to mention that the problem of the purity drop is attributed to the crystallization of the undesired enantiomer, often it is called spontaneous crystaUization and that the... 

Occurrence of Spontaneous Crystallization of an Unseeded Enantiomer. When we consider the purity drop on the phase diagram, it is the prerequisite that the seeds added to cause the preferential resolution are completely pure. However if the seeds are contaminated by the undesired enantiomer, the phenomena could be completely different. Since in general seeds are taken from a previous batch, they are likely to have been contaminated by the adhered mother liquor due to incomplete phase separation or by some non-equilibrium crystallization phenomena such as inclusion of mother liquor or agglomeration of crystalline particles. For the case of the former, drying of the crystals generates small particles of the undesired enantiomer which will then be introduced to a racemic solution as seeds. 

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