Solubility phase diagrams

The Kraft point (T ) is the temperature at which the erne of a surfactant equals the solubility. This is an important point in a temperature-solubility phase diagram. Below the surfactant cannot fonn micelles. Above the solubility increases with increasing temperature due to micelle fonnation. has been shown to follow linear empirical relationships for ionic and nonionic surfactants. One found [25] to apply for various ionic surfactants is ... 

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. 

This process is illustrated in a solubility phase diagram of three-component system as shown in Fig. 7.2b... 

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. 

FIGURE 7.1 Solubility phase diagrams of diastereoisomeric salts, (a) Ideal behavior (b) end solid-solution behavior (c) full solid-solution behavior and (d) double salt formation. 

FIGURE 7.2 Automated determination of a solubility phase diagram of a classical resolution, (a) Experimental setup with different ratios of p- and n-salt (dilution along the dashed lines) (b) solubilities at different starting... 

FIGURE 7.4 Partial solubility phase diagram determined by dilution experiments on a 1 1 diastereoisomeric mixture (dashed line). 

Solubility phase diagrams can provide very useful information as well. As shown in Figs. 2-20 and 2-21, the solubility curve can also be used to identify the regions if desirable compounds can be isolated as pure material,... 

Another sitnation arose dnring the preparation of the citrate salt as a result of the particnlar shape of the solubility phase diagram (two eutectics) and mainly the entectic composition. 

Finally, we discovered that L-(+)-tartaric acid was suitable for preparing the final salt and optically upgrading the enriched (5)-TH[3C. This will have the advantage to eliminate the issue associated with the optical purification of an enriched enantiomeric mixture ((5)-TH[3C.HCl or (5)-THpC.citrate) (solubility phase diagram with two eutectics) if the minimum required optical purity is not achieved. 

Solubility phase diagram reported for the diastereomer system (1 2 stoiehiometry) formed by ( )-phenylsueeinie aeid and (-)-proline, using ethanol as the solvent system. (The figure was adapted from data contained in Ref. 47.)... 

Several techniques such as the continuous variation method, mote ratio method, solubility phase diagrams, the direct measurement of complex molecular masses, etc. are available for a determination of the stoichiometry of intermolecular complexes. The commonly used mediod is the continuous variation method, which was originally proposed by Ostromislensky in 1911 [17] and modified by Job [18]. 

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. 

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

During crystallization, the degree of supersaturation is carefully controlled to obtain a desired polymorphic form and crystal habit. In general, crystallization occurs in the crystallization zone, which lies in between solubility line and precipitation line of a solubility phase diagram (Fig. 10.1). 

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...

Figure 7.9 Terna7 solubility phase diagrams of a target compound P and an impurity Imp in a solvent S at a given temperature. Shown is a solubility isotherm at a given temperature Tin case of comparable solubilities of P and Imp (xp.sat X mp sat) (a) arid a solubility of Imp much higher than that of P (xp sa, Ximp sat) (t>)-The maximum solubility of Imp in P in the solid state is given as X mp,s- A mixed costal of that composition is called Imp-saturated mixed...

Solubility phase diagram of propranolol hydrochloride system... 

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. 

Figure 4.5. HPAM (Calgon 835) solubility phase diagram as a function of sodium and calcium chloride concentrations Calgon 835 solutions, 23°C, pH 7-8, NaNj 200 ppm (after Zaitoun and Poitie, 1983).

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. 

---