Phase Diagram of a Chiral Substance Exhibiting Oiling Out in Cyclohexane

Abstract

This work investigates the ternary phase diagram of the enantiomers of ethyl-2-ethoxy-3-(4-hydroxyphenyl)propanoate (EEHP) in cyclohexane. The enantiomers of EEHP form a conglomerate, and both the pure enantiomer and the racemic mixture exhibit stable oiling out in cyclohexane. Our analysis shows that the ternary phase diagram of such a system assumes a unique structural evolution around the onset temperature of oiling out; that is, we found that the onset of oiling out strictly occurs through the emergence of a second liquid phase of racemic composition. Furthermore, we found that the further evolution of the ternary phase diagram, i.e., above the onset temperature of oiling out, is dictated by the properties of the phase diagrams pure enantiomer/solvent and racemic mixture/solvent. Our theoretical considerations are in excellent agreement with experimental measurements of EEHP in cyclohexane.

pH-Induced Precipitation Behavior of Weakly Basic Compounds: Determination of Extent and Duration of Supersaturation Using Potentiometric Titration and Correlation to Solid State Properties

“…This phenomenon has been reported to occur for a number of organic compounds (35)(36)(37)(38)(39)(40)(41)(42)(43)(44). L-L phase separation will always occur if the compound is above its melting point, or there is no crystalline form and the L-L miscibility point is exceeded.…”

Influence of Liquid‐Liquid Phase Separation on the Crystallization of L‐Menthol from Water

“…Measuring the solubility can be conveniently done by slowly heating a suspension of solids while monitoring the solution composition using, e.g., attenuated total reflection‐Fourier transform infrared spectroscopy (ATR‐FTIR) , . However, for molecules with extremely low solubilities, correlating infrared absorbance with solution concentration becomes infeasible , . In those cases, as well as for L ‐menthol in water, it is necessary to measure solubilities with methods such as HPLC.…”

“…Individually sampling each of two liquid phases in the presence of a solid phase can be extremely challenging experimentally , , and for this reason the composition of each phase was not measured directly. Instead, the temperature at which SLLE occurs, T SLLE , was determined by slowly heating a solid suspension until it transformed into a liquid‐liquid mixture.…”

“…Previously, by using knowledge obtained through a thermodynamic model , it was shown that, for a compound which has a solubility of several weight percent, it is possible to design a crystallization process yielding satisfactory productivity while avoiding LLPS. Many compounds, however, have solubilities that are in the order of micrograms per liter , , thus making the avoidance of LLPS physically possible but of no practical value due to the extremely low amount of solids which can be recovered. Under those circumstances, entering the LLPS region may be advantageous, since it allows access to significantly greater solute concentrations.…”

Preparation and characterization of amorphous, I and II forms of clopidogrel hydrogen sulfate

“…For instance, amorphous form, I form and II form have characteristic absorption bands at 1043.4 cm −1 , 1067.8 cm −1 and 867.9 cm −1 , respectively, while absorption band at 1752 cm −1 is common to all three forms. This phenomenon has been termed as oiling out, liquid-liquid demixing or liquid-liquid phase separation (LLPS) [24]. Figure 4 presents the solubility of the three forms of CHS in ethyl acetate at different temperatures, which in general increase with the temperature and decrease in the order: amorphous form > I form > II form.…”