Ternary solubility phase diagram

In addition to melting point phase diagrams, ternary solubility phase diagrams, in which the third compound is a liquid solvent, may also be applied to classify racemates (Fig. 6) at constant temperature. 

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. 

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 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.

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...

What is not considered here is partial miscibility in solid state also occurring in chiral systems. How this is represented in a ternary solubility phase diagram is shown in Section 7.2. 

Figure 3.30 Ternary solubility phase diagrams solubilities in the threonine/water system, only of the threonine and mandelic acid (MA) the upper part of the phase diagram is depicted...

The ternary solubility phase diagram of (S) - and (R) - propranolol hydrochloride in a mixed solvent of methanol and acetone was measured by isothermal method [25]. For isothermal method, enough amount of powder, namely lOfttO.lmg, was dissolved in the solvent of methanol in a test tube. Saturated solution samples were carefully withdrawn and filtered, and the concentration of which were analyzed by the HPLC system with employment of above-mentioned self-packed column. 

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 56.15. Ternary solubility phase diagram of racemic-compound-forming system. 

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. 

Crystallization is widely used for chiral purification. Development of such a crystallization method involves determination of racemate type, solvent screening, temperature selection, and definition of system composition. Construction of a ternary solubility phase diagram is instrumental during this process. However, constmcting phase diagrams in different solvents at various temperatures is time consuming and requires a large quantity of compound. Perhaps... 

To understand why solution experiments sometimes fail to produce cocrystal products, and why solvent-drop grinding experiments can work when performed on the same system, the 1 1 cocrystal formed by nicotinamide and frans-cinnamic acid (frans-(2E)-3-phenylacrylic acid) has been studied [56]. In this work ternary isothermal phase diagrams of the cocrystal system was used to understand the crystallization phenomena, and to deduce methodologies and for the experimental design of cocrystal preparation. Cocrystals are most likely to form from solutions in which the two reactants have similar degrees of solubility, and the success of solvent-drop grinding was explained in that crystallization took place in the region of low solvent mole fractions where the cocrystal would be more stable relative to the separated reactants. 

Figure 8.1 Solubility phase diagram for the ternary system Ca(0H)2-HjP04-H20 at 37°C [18],...

Figure 13.2 Pseudo ternary mixture phase diagram at constant temperature and pressure. The two comers on the base represent a liquid substrate and a gas reactant (having a limited solubility in the substrate) and the top corner corresponds to the solvent. The complete miscibility in (gas + solvent) and (substrate + solvent) ensures the presence of a homogenous region around the solvent corner that can only be obtained for compositions greater than...

However, in many ternary systems, all compounds have a degree of solubility in both phases (Figure 3.3.35). Typically, such ternary triangular phase diagrams are characterized by two liquid pairs that are completely miscible in all proportions, for example, water-ethanol and ethanol-benzene (Figure 3.3.35a), or by two pairs that are only partially miscible, for example, heptane-aniline and aniline-methylcyclo-hexane (Figure 3.3.35b). 

Once the solubility and coexistence curves have been determined, the complete ternary phase diagram may be constructed. This procedure is illustrated by the example shown in Fig. 28. The following parameters have been used ... 

Case I. At sufficiently low pressures, the solubility curve does not intersect the coexistence curve. In this case, the gas solubility is too low for liquid-liquid immiscibility, since the coexistence curve describes only liquid-phase behavior. Stated in another way, the points on the coexistence curve are not allowed because the fugacity f2L on this curve exceeds the prescribed vapor-phase value f2v. The ternary phase diagram therefore consists of only the solubility curve, as shown in Fig. 28a where V stands for vapor phase. 

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 25 shows the ternary phase diagram (solubility isotherm) for an unsolvated racemic compound. Examples of this type include benzylidenecamphor in methanol, or /V-acetylvaline in acetone [141]. In Fig. 25, A and A represent the...

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. 

Solubilities of Trichlorides in Water as Taken from Ternary Phase Diagrams... 

Chapter 18 - The determination region of solubility of methanol with gasoline of high aromatic content was investigated experimentally at temperature of 288.2 K. A type 1 liquid-liquid phase diagram was obtained for this ternary system. These results were correlated simultaneously by the UNIQUAC model. By application of this model and the experimental data the values of the interaction parameters between each pair of components in the system were determined. This revealed that the root mean square deviation (RMSD) between the observed and calculated mole percents was 3.57% for methylcyclohexane + methanol + ethylbenzene. The mutual solubility of methylcyclohexane and ethylbenzene was also demostrated by the addition of methanol at 288.2 K. 

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