Crystallization resolution phase diagrams

Although fractional crystallization has always been the most common method for the separation of diastereomers. When it can be used, binary-phase diagrams for the diastereomeric salts have been used to calculate the efficiency of optical resolution. However, its tediousness and the fact that it is limited to solids prompted a search for other methods. Fractional distillation has given only limited separation, but gas chromatography and preparative liquid chromatography have proved more useful and, in many cases, have supplanted fraetional crystallization, especially where the quantities to be resolved are small. 

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. 

Figure 13. Schematic phase diagram of water s metastable states. Line (1) indicates the upstroke transition LDA —>HDA —>VHDA discussed in Refs. [173, 174], Line (2) indicates the standard preparation procedure of VHDA (annealing of uHDA to 160 K at 1.1 GPa) as discussed in Ref. [152]. Line (3) indicates the reverse downstroke transition VHDA—>HDA LDA as discussed in Ref. [155]. The thick gray line marked Tx represents the crystallization temperature above which rapid crystallization is observed (adapted from Mishima [153]). The metastability fields for LDA and HDA are delineated by a sharp line, which is the possible extension of a first-order liquid-liquid transition ending in a hypothesized second critical point. The metastability fields for HDA and VHDA are delineated by a broad area, which may either become broader (according to the singularity free scenario [202, 203]) or alternatively become more narrow (in case the transition is limited by kinetics) as the temperature is increased. The question marks indicate that the extrapolation of the abrupt LDA<- HDA and the smeared HDA <-> VHDA transitions at 140 K to higher temperatures are speculative. For simplicity, we average out the hysteresis effect observed during upstroke and downstroke transitions as previously done by Mishima [153], which results in a HDA <-> VHDA transition at T=140K and P 0.70 GPa, which is 0.25 GPa broad and a LDA <-> HDA transition at T = 140 K and P 0.20 GPa, which is at most 0.01 GPa broad (i.e., discontinuous) within the experimental resolution.

For convenience, a phase diagram of a pair of diastereomeric crystals is ordinarily studied in detail, and the mechanism of the diastereomeric resolution is interpreted in terms of the thermodynamic and physical properties of the bulk of the diastereomeric crystals.4,7-10 Such studies reveal the importance for diastereomeric resolution of the type of mixture of diastereomers in a target system. There are three types of diastereomer mixtures an eutectic mixture, a 1 1 addition compound, and a solid solution. To achieve successful resolution, it is essential that the mixture of the diastereomeric crystals of a target racemate with a resolving agent be an eutectic mixture. The classic studies are thoroughly reviewed by Collet and co-workers.4,12... 

Phase diagrams with monotropic transformation or enantiotropic transformation have been discussed. " Quite interesting is the transformation of the racemic compound into a conglomerate since this phenomenon can be used for purification via crystallization, as described for nimodipine. DSC is applied for the establishment of phase diagrams, for the determination of thermodynamic data, for the purity determination, or for the monitoring of industrial resolutions. For the establishment of phase diagrams it is suitable to add spectroscopic or crystallographic methods. ... 

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. 

Thermal broadening of an electronic transition results from the population of additional vibrational levels of the electronic ground state illustrated by the potential energy diagram in fig. 3.14. Conversely, spectral features may be narrowed, and better resolution of absorption bands achieved, by performing crystal field spectral measurements at low temperatures. Under these conditions, vibrational peaks may contribute to fine structure observed on electronic absorption bands of transition metal-bearing phases, particularly in low temperature spectra. 

Figure 5. (a) High resolution temperature-pressure diagram in the vicinity of the N-A-C multicritical point in 4-n-heptacylphenyl-4 -(4"-cyanobenzoyloxybenzoate). The solid lines are computer fits of data evaluated with equations representing the NA, NC, and AC phase boundaries, respectively, (b) The universal temperature-concentration plot showing the data for four binary liquid crystal systems. (From [100], reproduced by permission of American Physical Society.)... 

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