Conglomerate system

High-pressure liquid chromatographic (HPLC) analysis performed with a chiral mobile phase (57,58) confirmed in all the conglomerate systems that the S inhibitors are selectively occluded only in the bulk of the S substrate crystals, typically in amounts of 0.5-1% (and, by symmetry, occlusion of R occurs only in R crystals). The selective adsorption causes, furthermore, a drastic decrease in the growth (and possibly nucleation) rate of the affected enantiomer, leading to efficient kinetic resolution various conglomerate systems have been resolved by this method (54). 

Conglomerates and racemates can be easily distinguished from each other on the basis of their melting point phase diagrams [25]. A conglomerate system will exhibit a single eutectic minimum in its phase diagram at the mole fraction of 0.5, since at this enantiomeric ratio the system will consist of an equimolar mixture of two crystalline enantiomers that melts as if it were a pure system. Qn the other hand, a racemate system will exhibit two eutectics on either side of the mole fraction of 0.5 since both enantiomers will be foimd in the unit cells of the crystallized solid. 

A theoretical explanation has been developed to explain the effect of chiral impurities on the crystallization rates of the enantiomorphic components of a conglomerate system [31]. The theory provides the time required to complete the crystallization of the separated enantiomers, suggests that one might be able to obtain an enantiomerically pure product even if the chiral impurity was less than enantiomerically pure, and even provides information regarding the particle size distribution. The model was tested on the crystallization of (D,L)-glutamic acid that was carried out in the presence of a resolved (L)-lysine impurity. 

An example of the type of melting point phase diagram that is typical for a conglomerate system is shown in Fig. 9.2, which illustrates the phase diagram reported for methyl diacetyltartrate [32]. Below the eutectic temperature of 79 °C, the system will exist as a mixture of solid D-enantiomer and L-enantiomer. At the exact composition of the racemic mixture (X = 0.5), the system will exist entirely in the liquid phase above the eutectic temperature. At mole fractions where the amount of (L)-enantiomer exceeds that of the (D)-enantiomer, the system will exist as an equilibrium mixture of racemic liquid and solid (L)-enantiomer. 

To illustrate how a racemate system can be turned into a conglomerate system, and to demonstrate how one may recognize the existence of a conglomerate system, we will consider the example of ibuprofen, or 2-(4-isobutylphenyl)propanoic acid. The single crystal structures of enantio-merically pure [44] and racemic [45] ibuprofen have been published, and the powder diffraction patterns of the enantiomerically pure and racemic forms are shown in Fig. 9.3. The existence of a conglomerate system is indicated if the diffraction patterns of enantiomerically pure and racemic... 

Care must be observed in the interpretation of a melting point phase diagram for those instances where the eutectic temperatures are located close to the equimolar composition, as such systems could be erroneously interpreted as indicating the existence of a conglomerate system. An example of this type of behavior is shovm in Fig. 9.6 for the ethyl diace-tyltartrate system, where a eutectic temperature of 42 °C was found for a d-enantiomer composition of 55.7 mole-percent [32]. On the other hand, when the eutectic temperatures are close to the melting points of the pure enantiomers, the phase diagram could be mistaken for that of a solid solution. An example of this behavior is shovm in Fig. 9.7 for the methyl dibenzoyltartrate system, where a eutectic temperature of 130.4 °C was... 

Since conglomerate systems consist of totally independently formed enantiomer crystals and are therefore mere physical mixtures of the enantiomer components, these constitute a binary system. Such binary mixtures are easily described by the phase rule and can be profitably characterized by their melting point phase diagrams [10]. Since the components of a conglomerate racemate will melt indepen-... 

An alternative approach for the characterization of conglomerate systems is through the use of ternary phase diagrams, where one component is the solvent and the compound solubility is used as the observable parameter [10,32]. The racemic mixture is found to be more solu-... 

Fig.2 Ternary phase equilibrium at constant pressure and temperature for racemic mixture (conglomerate) systems...

Figure 7.10. Flow diagram for the continuous crystallization of a conglomerate system. After Stahly and Byrn, 1999)...

FIGURE 56.10. Binary phase diagram of conglomerate system. 

The compositions of the solid phase and that of the liquid phase are interdependent, so establishment of a true equilibrium would require that there be a continuous change in the composition of the solid phase as a whole concomitantly with that of the liquid phase during the process of melting, which is kineticaUy unachievable. Nevertheless, the phase diagrams constructed for a conglomerate system and a pseudoracemate system should be different enough to distinguish the two systems. 

Solubility data at the eutectic point for a conglomerate system (equivalent to the solubdity of the conglomerate) can be determined experimentally by measuring the total concentration in a saturated solution equilibrated with both enantiomers. The solubihty of each enantiomer should be half of this value. Solubihty data at the eutectic point for a racemic-compound-forming system, hence the eutectic ee, can be determined by measuring the concentrations of each enantiomer in a saturated solution, which is in equilibrium with a solid mixture of one enantiomer and the racemic compound. Because of the advancement of chiral HPLC in the past years, satisfactory results can be readily obtained and with a reasonable amount of material if an appropriate solvent is chosen. The same approach is applicable for obtaining the solubility of a racemic compound, where the solubility equals the total concentration of R and S in the supernatant saturated with racemic compound. If no material with ee of 0% is available, then the solubility of the racemic compound can be calculated from the following equation ... 

Conglomerate System For a conglomerate system, the minor enantiomer can be dissolved in the supernatant and the pure product retained in the solid phase. The minimum amount of solvent required to dissolve all of the minor enantiomer is given by the following equation ... 

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