Enantiomers, phase solubility diagrams

S.K. Dwivedi, S. Sattari, F. Jamali, A.G. Mitchell, Ibuprofen racemate and enantiomers phase diagram, solubility, and thermodynamic studies, Int. J. Pharm. 87 (1992) 95-104. 

Figure 3.29 presents the relation between the binary melt phase diagrams and an isothermal slice of the ternary solubility phase diagrams (introduced in Section 3.1.4). Since the two enantiomers of a chiral system have same melting points and melting enthalpies, their melt phase diagrams are symmetrical to the 1 1 (i.e., racemic) composition. The same applies to the solubility diagrams of the enantiomers as shown in Figure 3.29. Therefore, in general only one haF of the phase diagram has to be measured.

To construct a triangular diagram consisting of two enantiomers and the solvent at constant temperature requires the determination of the concentration of the saturated solutions as a function of the total composition of the system, and the number and nature of the solid phases in equilibrium with the saturated solution. The determination of the solubility of mixtures of enantiomers is... 

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].

Figure 26 shows the ternary phase diagrams (solubility isotherms) for three types of solid solution. The solubilities of the pure enantiomers are equal to SA, and the solid-liquid equilibria are represented by the curves ArA. The point r represents the equilibrium for the pseudoracemate, R, whose solubility is equal to 2Sd. In Fig. 26a the pseudoracemate has the same solubility as the enantiomers, that is, 2Sd = SA, and the solubility curve AA is a straight line parallel to the base of the triangle. In Figs. 26b and c, the solid solutions including the pseudoracemate are, respectively, more and less soluble than the enantiomers. 

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. 

Solubility of racemic praziquantel was determined in MeOH and 2-PrOH in the temperature range between 0 °C and 40 °C. A ternary phase diagram of praziquantel enantiomers and the MeOH system was also determined (06CH259). The solubility phase and binary melting-point phase diagrams were determined. Experimental and predicted aqueous solubility of praziquantel was reported (07CPB669,08SQE191). Dissolution of praziquantel... 

Less than 1% of racemic species are pseudoracemates, which show typical phase diagrams of continuous solid solutions. Figure 2c shows the three types of melting phase diagrams of pseudoracemates, which comprise ideal solid solutions, solid solutions with positive deviations from ideality, and solid solutions with negative deviations from ideality, respectively [13]. In real systems, the enantiomers and the racemic compound may display a small mutual solubility, even if they show eutectic behavior, which corresponds to terminal solid solutions for which the phase diagrams are shown in Figs. 2d and 2e. 

Figure 6 Ternary phase diagram showing the solubility of the racemic species (a) conglomerate, C, (b) racemic compound, R, (c) pseudoracemate, P i, ideal ii, positive deviations iii, negative deviations. D and L represent the enantiomers, S represents the solvent, at constant temperature. (From Ref. 10. Reproduced by permission of John Wiley and Sons.)...

When the rate of drug absorption is controlled by the dissolution rate, the bioavailability of a drug increases with an increase of its dissolution rate. The dissolution rate is proportional to the solubility, regardless of dissolution mechanism. The solubilities of the two enantiomers are identical in an achiral solvent. The theoretical ternary solubility phase diagrams of racemates are represented by Fig. 6. The solubility phase diagram of a conglomerate (Fig. 6a) shows eutectic behavior. 

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]. 

A mixture of d and l enantiomers in the presence of a solvent S constitutes a ternary system in whieh the equilibria are best represented on a triangular diagram (see section 4.6.3). The effects of temperature on solubility and phase change can also be ineluded. Figure 7.9a shows the transition of a racemic compound R, stable at the lower temperatures t and to a conglomerate at the higher temperature t. ... 

Phase diagrams such as those depicted in Figures 7.8 and 7.9 can readily be construeted by measuring the solubilities of a range of mixtures of the two enantiomers and determining their equilibria by methods described in section 4.5. At all times during equilibrium determination undissolved solid must... 

However, often the phase diagrams required are not known in particular for new substances in the fine chemical and pharmaceutical fields. Even more hard to find are ternary solubility phase diagrams that describe equilibria of two substances in a solvent such as the target compound and an impurity in a solvent of choice or the two enantiomers of a chiral system in a solvent. Often one faces a lack of consistent solubility data for the substance of interest. Experimental determination of solubilities is a tedious and time-consuming work and requires a sufficient amount of substance that is often not available in an early stage of development. Also, usually a combination of different analytical techniques is necessary to obtain both the solubility and the identity of the solid phase in equilibrium. 

Impurities can also affect the solubility of a solute of interest. Here, both a solubility enhancement and a solubility decrease occur. When electrolytes are involved, the terms salting-in and salting-out apply. Small impurity contents might be evaluated together with the solvent. In presence of higher impurity contents or in cases where the impurity is readily available in sufficient amounts, it should be considered as a third component in the system. Then, SLE data in the ternary system of the target compound, the impurity, and the solvent/solvent mixture have to be measured and instead of a binary a ternary (solubility) phase diagram applies. The representation and application of ternary SLE will be addressed in Section 3.3.7 on the example of enantiomers. 

Figure 3.29 The relation of binary melt phase diagrams and ternary solubility phase diagrams of enantiomers. The latter are represented as isothermal slices at an...

The construction of a ternary solubility phase diagram for two solid phases in equilibrium with one solution was discussed in detail by Jacques et al. in the context of solubility phase diagrams of enantiomers in achiral solvents,2 where the method of algebraic extrapolation or wet residues is used. The biggest challenge with this classic method is the avaUabUity of pure components, enantiomers, or diastereomeric salts. The discontinuous isoperibolic thermal analysis (DITA) method developed by Marchand et al.22 overcame this barrier. In the DITA method, a mixture of an equal amount of diastereomeric salts is used. 

FIGURE 56.17. Ternary solubility phase diagram of conglomerate system enantiomer forms solvate. 

FIGURE 56.18. Ternary solubility phase diagrams of racemic compound-forming systems (a) racemic compound forms solvate, (b) enantiomers form solvate, and (c) both enantiomers and racemic compound form solvates. 

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