Ternary solubility diagrams

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. 

Fig. 3 Ternary diagram of solubility of a compound in a ternary mixture with linear solubility response. (Inset) Concentration of drug in compositions with constant concentration of B. The composition of the solute is the constant concentration of B, the concentration of A in the abscissa, and the complement concentration of the third component. The drug solubility response is linear in the A concentration in this case.

The way in which the solubility products were evaluated from the primary data could not be followed in such detail that a critical evaluation could be made. This comment applies in particular to the calculations performed on data from ternary solubility diagrams. The results obtained by Kumok and Batyreva are therefore mentioned in Chapter V but not accepted. 

Special Effects Accomplished by Formulating with Ternary Solubility Diagrams... 

Following the technique of solvent selection by solubility maps and ternary solubility diagrams, the coatings formulator can adapt solvent blends for epoxy resins to obtain lower viscosities and improved drying rates. It is obvious that lowering the solvent cost, conforming to air pollu-... 

This chapter demonstrates how to calculate phase diagrams and solubility isotherms for binary and ternary supercritical mixtures. As Johnston has pointed out (Wong, Pearlman, and Johnston, 1985 Johnston, Peck, and Kim, 1989), no single model will work for all situations. As the equations describing molecular interactions in dense fluids become more accurate, we can expect our abilities to model complex phase behavior to improve. At present, using a cubic equation of state or a lattice-gas equation appears to offer the best compromise between accuracy and ease of application. 

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. 

Fig. 16.5 Ternary solubility diagram for n-propanol/water/n-propyl acetate (% w/w, 30°C).

Fig. 16.6 Ternary solubility diagram for -propanol/water/cyclohexane (% w/w, 35 °C).

Fig. 16.32 Ternary solubility diagram showing the temperature dependence of the phase behaviour of ethyl acetate/ water/ethanol, indicating that the ternary azeotrope is two phase at 20 °C and single phase at 70 °C.

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. 

This type is exemplified by the system chlorobenzene (A)-water (B)-methyl ethyl ketone (C), where A and C arc completely soluble, while the pairs A-B and B-C show only limited solubility. Refer to Fig. 10.5a, a typical isotherm. At the prevailing temperature, points K and J represent the mutual solubilities of A and B and points H and L those of B and C. Curves KRH (A-rich) and JEL (B-rich) are the ternary solubility curves, and mixtures outside the band between these curves form homogeneous single-phase liquid solutions. Mixtures such as Af, inside the heterogeneous area, form two liquid phases at equilibrium at E and R, joined on the diagram by a tie line. The corresponding distribution curve is shown in Fig. 10.5i>. 

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... 

McKetta "Survey of Solubility Diagrams for Ternary and Quarternary Liquid Systems," Bureau of Engineering Research, Special Publ. Nr. 30, University of Texas, Austin, 1959. 

Fig. 2. Flow diagram of ternary wax mixtures of (A) Comeflus paraffin 124, 91.2% flow (B) Ross ceresin, 1573/1 85.7% flow and (C) Stevenson spermaceti, 0.2% flow, at 37°C. Numbers in the diagram represent percent flow the dotted area shows where the waxes are not soluble in each other in the...

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