Eutectic Point Measurement

The eutectic point can be measured by a number of methods. Two simple and generally applicable methods and their shortcomings are discussed. 

Solution concentration and solid phase analysis Measurement of the solution concentration of each co-crystal component when the solution is 

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Eutectic points and stability regions for co-crystals of carbamazepine-4-aminobenzoic acid in ethanol are shown in Figure 11.13(a) and (b). This system has two co-crystals with different stoichiometries (1 1) and (2 1) thus, there are four eutectic points. Variations in [drug] u relative to [drug] at saturation in the absence of co-former provide a measure of co-crystal and drug solubility dependence on solution phase interactions. Co-crystal thermodynamic stability can be quantitatively predicted by combining eutectic point measurements with equations that describe solution behavior. " ... 

How eutectic point measurement leads to information about co-crystal solubility under stoichiometric solution conditions includes ... 

The DSC procedure does not directly measure AT, but can be used to calculate it from the melting curve. At the eutectic point, all of B is in the liquid phase. During the melting of A after the eutectic point the concentration of B varies in the liquid phase. This causes the broadening of the DSC curve. With no solid... 

The freezing points of biochemical products containing hygroscopic molecules (e.g. sugars, protein complexes) are well below zero by effect of some water molecules being tightly bound to molecules of the dissolved product. Eutectic points are usually determined from electrical resistivity measurements. 

The phase diagram of the ternary system KF—KCl—KBF4 was measured by Patarak and Danek (1992). The system is simple eutectic with the coordinates of the eutectic point of 19.2 mole % KF, 18.4 mole % KCl, 61.4 mole % KBF4, and the temperature of eutectic crystallization of 422°C. 

The electroreduction of zirconium halides in alkali halide melts has led to the measurement of reversible potentials (Table XXV) in the temperature range 670°-750°C (550). Phase rule studies of the mixed systems preceded the cell studies and revealed that the phase diagrams of the KCl-ZrCl2 and NaCl-ZrCl2 systems were of the simple eutectic type. The liquidus curves of these binary systems were established by freezing point measurements. The melting point of pure zirconium dichloride was found to be 722° 1°C. In the potassium chloride-zirconium dichloride system, the eutectic is found at 698° 1°C at... 

The peritectic melting temperature of SiC was set to 2818 K and the eutectic temperature between (Si) and SiC to 1677 K. However, these data were significantly corrected later by Kleykamp and Schumacher (1993) [85] due to literature assessment and their own experimental results for temperatures between 1700 and 3300 K. The peritectic temperature for SiC was measured to occur at 3103 K 40 K. This temperature confirms the data given by Scace and Slack (1959) [79] and Kieffer et al. (1969) [89]. The (degenerated) eutectic point between (Si) and SiC was set to 1686 K 1 K (melting point Si 1687 K) and 0.02 at.%. Additionally, the liquidus on the Si-rich side of the system was measured. Data provided by DoUoff (1960) [80] scatter significantly from data... 

Mixture Melting-Point Measurements. Observe a series of evacuated mixture melting points (see Chapter 4) with isomer ratios of 75 25,50 50, and 25 75. These values will allow you to estimate the eutectic temperature of this system. This same technique is used in Experiment [29A] to aid in identifying the isolated product, 2,5-dichloronitrobenzene, which has a melting point only 3 °C higher than 1,4-dichlorobenzene, the starting material in this nitration reaction. 

For a simple eutectic and a racemic compound-forming system in Figure 3.30, the measured ternary phase diagrams of the amino acid threonine and the fine chemical mandelic acid, both in water as solvent, are exemplarily shown. The diagrams contain equilibrium data measured in isothermal experiments as described in Section 3.3.5.2. Different temperatures were applied. All solubihties are related to the solid phases given, no solvate was found. Most points measured refer to... 

Figure 11.14 Phase diagrams for theophylline-citric acid (THP-CTA) anhydrous and co-crystal hydrate in water at 25 °C. Eutectic points are indicated by (THP hydrate/THP-CTA hydrate), Ej (THP-CTA hydrate/THP-CTA anhydrous) and Ej, (THP-CTA anhydrous and CTA hydrate). Solubilities of THP hydrate and CTA hydrate are indicated by a and b in each plot. (a) Phase solubility diagram generated from measured eutectic points and models that describe co-crystal solubility behavior, (b) Schematic triangular phase diagram showing the stability domains for anhydrous and hydrated co-crystals with co-formers that modulate the water activity. Stability regions for the crystalline phases are 1, crystalline drug hydrate 2, co-crystal hydrate 3 anhydrous co-crystal 4, co-former hydrate 5, crystalline drug hydrate/co-crystal hydrate 6, anhydrous/hydrated cocrystals 7, anhydrous co-crystal/hydrated co-former.

If co-crystals are to solve solubility problems one must assess their true or thermodynamic solubility so that development strategies are guided by the fundamental properties of co-crystals. Measuring the solubility of co-crystals that generate supersaturation of the parent drug is often experimentally impossible due to conversion. Eutectic points, described in Section 11.4, provide a measure of co-crystal solubility under thermodynamic equilibrium conditions. The solution at the eutectic point is saturated with co-crystal and solution concentrations represent experimentally accessible thermodynamic solubility values. Once co-crystal solubility is determined at the eutectic, the solubility under different solution conditions (pH, co-former, micelle concentration) can be obtained from solubility models that consider the appropriate solution phase equilibrium expressions. 

The melting point of the LiCl-KCl eutectic was measured and was found to be close to 352 2 °C. This value is consistent with previous determinations (352 °C [17], 354 C [18]). This value was used to check the temperature calibration of the thermal analyser. On the DTA trace, at lower temperature, no other peak was detected due to the presence of either oxides or hydroxides, for example at 270 °C, which corresponds to the eutectic temperature in the reciprocal (Li, K//0, H) system [19] or to a solid solution transition. 

Solubility data at the eutectic point for a conglomerate system (equivalent to the solubdity of the conglomerate) can be determined experimentally by measuring the total concentration in a saturated solution equilibrated with both enantiomers. The solubihty of each enantiomer should be half of this value. Solubihty data at the eutectic point for a racemic-compound-forming system, hence the eutectic ee, can be determined by measuring the concentrations of each enantiomer in a saturated solution, which is in equilibrium with a solid mixture of one enantiomer and the racemic compound. Because of the advancement of chiral HPLC in the past years, satisfactory results can be readily obtained and with a reasonable amount of material if an appropriate solvent is chosen. The same approach is applicable for obtaining the solubility of a racemic compound, where the solubility equals the total concentration of R and S in the supernatant saturated with racemic compound. If no material with ee of 0% is available, then the solubility of the racemic compound can be calculated from the following equation ... 

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