Solubility, conglomerates

The Chilean nitrate deposits are located in the north of Chile, in a plateau between the coastal range and the Andes mountains, in the Atacama desert. These deposits are scattered across an area extending some 700 km in length, and ranging in width from a few kilometers to about 50 km. Most deposits are in areas of low rehef, about 1200 m above sea level. The nitrate ore, caUche, is a conglomerate of insoluble and barren material such as breccia, sands, and clays (qv), firmly cemented by soluble oxidized salts that are predominandy sulfates, nitrates, and chlorides of sodium, potassium, and magnesium. Cahche also contains significant quantities of borates, chromates, chlorates, perchlorates, and iodates. 

Chemical development Proof of structure and configuration are required as part of the information on chemical development. The methods used at batch release should be validated to guarantee the identity and purity of the substance. It should be established whether a drug produced as a racemate is a true racemate or a conglomerate by investigating physical parameters such as melting point, solubility and crystal properties. The physicochemical properties of the drug substance should be characterized, e.g. crystallinity, polymorphism and rate of dissolution. 

Conglomerate crystallization in the above case indicates that the inclusion approach may be further extended into the realm of the salt-type associates. Such an attempt is especially interesting due to the obvious role in enantiomer separation which relies heavily on the solubility difference of the enantiomeric salts under certain circumstances 137). 

Fig. 21 Three-dimensional representation of a ternary system of two enantiomers in a solvent, S. One of the faces of the prism (at left) corresponds to the binary diagram of D and L (here a conglomerate). Shaded area isothermal section representing the solubility diagram at temperature T0. (Reproduced with permission of the copyright owner, John Wiley and Sons, Inc., New York, from Ref. 141, p. 169.)...

Figure 24 shows the ternary phase diagram (solubility isotherm) of an unsolvated conglomerate that consists of physical mixtures of the two enantiomers that are capable of forming a racemic eutectic mixture. It corresponds to an isothermal (horizontal) cross section of the three-dimensional diagram shown in Fig. 21. Examples include A-acetyl-leucine in acetone, adrenaline in water, and methadone in water (each at 25°C) [141].

If the molecular species of the solute present in solution is the same as those present in the crystals (as would be the case for nonelectrolytes), then to a first approximation, the solubility of each enantiomer in a conglomerate is unaffected by the presence of the other enantiomer. If the solutions are not dilute, however, the presence of one enantiomer will influence the activity coefficient of the other and thereby affect its solubility to some extent. Thus, the solubility of a racemic conglomerate is equal to twice that of the individual enantiomer. This relation is known as Meyerhoffer s double solubility rule [147]. If the solubilities are expressed as mole fractions, then the solubility curves are straight lines, parallel to sides SD and SL of the triangle in Fig. 24. 

If a solute of the general formula AX (A is the chiral ion and X is an achiral ion) dissociates completely into ions once dissolved, then the solubility of the racemic conglomerate, SR, is equal to n%V2-SA (where SA is concentration of A in a solution saturated with AX ). If the solute is of the type AX, then 5 = V2-5a. The subscript n refers to the achiral ion and may be fractional, and so A2X must be represented by AXi/. If dissociation of AX is incomplete, SA lies between n i/2-SA and 2SA. For weakly dissociated electrolytes (such as carboxylic acids), SR is approximately 2SA. 

The conglomerate shows a lower melting point (and hence, a higher solubility) than the individual enantiomers. From a melt or a solution with an enantiomeric ratio +1 1, the excess enantiomer crystallizes in pure form. The racemic compound may have a lower (curve 1) or a higher (curve 2) melting point (or solubility) than the corresponding enantiomers the eutectic mixture (E), however, always lies at a minimum. Finally, crystallization of pseudoracemates always yields enantiomerically impure samples. 

If an enantiomer has a greater affinity for molecules of like configuration, then two sets of crystals will be formed, one set composed only of the (+) form and the other composed only of the (—) form. This racemic mixture is called a conglomerate because it is a mixture of two different types of crystals. Moreover it behaves as a typical mixture—the melting point is lower titan the pure enantiomeric components and the solubility is higher (Figure 6.2). This is a relatively rare situation. 

If ionic component X is the same in the conglomerate salt A+X , and the salt is dissociated into the ions, the solubility ratio of the racemate and active component Sr/Sa becomes equal to -f 2. The solubility phase diagram in this case is shown in Figure 4a, where the operation area becomes wider, and operations become easier. 

The limitations of the solubility method for surface measurement are readily apparent. Mineral particles are usually conglomerate, or composed of crystals often loosely bound. A strong acid such as hydrofluoric acid tends to split up the particles or penetrate so far that the true surface is exaggerated. Another difficulty concerns the assumption that all portions of a given particle-surface dissolve uniformly this is not the case. The solubility of indentations or discontinuities is not uniform, especially since such points have occluded gases which are not affected. In most instances these factors are probably averaged out, and excellent approximations of the true surface may be made but instances will undoubtedly arise where they are of great importance. 

TABLE 9.2 Solubilities of separated enantiomers and racemic mixtures of conglomerate materials... 

In general, kinetic resolution requites the presence of a racemic mixture (conglomerate) and the absence of a (generally lower-solubility) racemic compound (both enantiomers in the crystal lattice). This is not always the case, however, and depending on the relative rates of nucleation and crystal growth of the respective forms, a kinetic (nonthermodynamic) isomer separation can sometimes be effected even when a racemic compound is possible. In the case of solid solution of the enantiomers (no lattice fit requirement), an equilibrium process will essentially always be requited. 

Even in the best case, some racemic product is produced and must be separated out. This separation is easy or hard, depending on the nature of the racemate. If the racemic modification has a different crystalline form to that of the pure d or l, then separation of the pure excess enantiomer will be inefficient. If one achieves a 90% ee value, then it is quite possible to get out only 75-80% pure enantiomer. With lower ee values, the losses become prohibitive. For such a system, a catalyst of very high efficiency must be used. Unfortunately, most compounds are of this type their racemic modifications do not crystallize as pure d- or l-forms. If, on the other hand, the racemic modification is a conglomerate or an equal mix of d- and L-crystals, then recovery of the excess the L-form can be achieved with no losses. Since the l- and D,L-forms are not independently soluble, a 90% ee value easily gives a 90% recovery of pure isomer. In our L-dopa process, the intermediate is just such a conglomerate and separations are efficient. This lucky break was most welcome. If one thinks back, ours was the same luck that Pasteur encountered in his classical tartaric acid separations, 150 years ago. 

A description of an amplification procedure based on the different solubility of the D-enantiomer and that of the corresponding d, L-racemate of ribonucleosides follows. When the melting points and solubilities of crystalline d, L-ribonucleosides and the pure D-ribonucleoside were determined, it was found that solution-based amplification of a slight ee of D-cytidine and D-adenosine, in a mixture with the d, L-racemates, is sufficiently large to produce solutions with at least 99% ee of the D-enantiomer (Breslow et al. 2010 and references cited therein). The 96% excess of D-uridine could also be sufficient to allow for the selection of the d isomer in solution under prebiotic conditions. In contrast, d, L-ribose itself forms a solid solution and d, l-guanosine a conglomerate (Breslow et al. 2010). This work is based on the mechanism for the amplification of fluctuations in racemic mixtures of the corresponding compounds (Morowitz 1969). 

If an unsaturated solution, the composition of which is represented by a point in the field to the right of the solubility curves, is cooled down, the result obtained will differ according as the composition of the solution is the same as that of a cryohydric point, or of a melting-point, or has an intermediate value. Thus, if a solution represented by % is cooled down, the composition will remain unchanged as indicated by the horizontal dotted line, until the point D is reached. At this point, dodecahydrate and heptahydrate will separate out, and the liquid will ultimately solidify completely to a mixture or conglomerate of these two hydrates the temperature of the system remaining constant until complete solidification has taken place. If, on the other hand, a solution of the composition is cooled down, ferric chloride dodecahydrate will be formed when the temperature has fallen to that represented by C, and the solution will completely solidify, without alteration of temperature, with formation of this hydrate. In both these cases, therefore, a point is reached at which complete solidification occurs without change of temperature. 

Application to the Characterisation of Racemates.— The form of the isothermal solubility curves is also of great value for determining whether an inactive substance is a racemic compound or a conglomerate of equal proportions of the optical antipodes. ... 

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