Phase Diagram of a Chiral Substance Exhibiting Oiling Out. 2. Racemic Compound Forming Ibuprofen in Water

Abstract

This work investigates the ternary phase behavior of the two enantiomers of ibuprofen and water. The two enantiomers crystallize as a racemic compound and exhibit a thermodynamically stable liquid–liquid phase separation (LLPS), which extends over the entire enantiomeric composition range. First, the generic phase behavior of racemic compound forming systems exhibiting a stable LLPS is derived by exploiting the consolidated knowledge of conglomerate forming systems obtained in the first part of this series. Below the onset temperature of the LLPS, the system behaves like a typical racemic compound forming system. As for conglomerate forming systems, the onset of the LLPS is found to occur through a ternary monotectic equilibrium, where a new, solute-rich liquid phase emerges inside each solid–solid-liquid phase region. Then, the ternary phase diagram of the ibuprofen/water system in the temperature range from 40 to 82 °C is presented together with the outcome of a thorough experimental investigation. Our theoretical considerations are in excellent agreement with experimental results.

Solubility and Some Crystallization Properties of Conglomerate Forming Chiral Drug Guaifenesin in Water

“…For both racemic and enantiopure substances, visually a slightly pronounced oiling‐out in aqueous solutions was observed under cooling. This phenomenon was under consideration in recent works, and is frequently observed for “organic compound–water” systems. This can be the reason of such an extreme solubility behavior of compound 1 .…”

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.…”

Separation of conglomerate forming enantiomers using a novel continuous preferential crystallization process

“…Fortunately, the case of solid solutions (Figure c), where crystals can contain any composition of R and S enantiomers and which are hardest to separate, is rarely encountered for organic molecules. Apart from the ideal cases shown in Figure , there are numerous (combinations of) nonidealities possible, for example, the presence of a metastable conglomerate in racemic compound forming systems, partial solid solutions, the presence of liquid‐liquid equilibria, and the presence of (metastable) polymorphs …”