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.

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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.

A methodology for the design of cooling crystallization processes for chiral resolution from nonracemic initial solutions is presented. Such processes are encountered when chiral resolution is attained by hybrid processes, where the crystallization step is preceded by a pre-enrichment step accomplished by either asymmetric synthesis or another separation technique. The work focuses on substances that crystallize as conglomerates and accounts for the occurrence of oiling out, i.e., an undesired liquidÀliquid phase separation during crystallization. The generic ternary phase diagrams for conglomerate-forming systems with and without oiling out are derived. This knowledge is then applied to identify suitable operating conditions for chiral resolution. As crystallization is started from saturated solutions, the crystallization process is characterized by three parameters: the initial enantiomeric excess and the initial temperature, which together implicitly define the position of the operating point in the phase diagram, and the final operating temperature, which defines the composition and the amount of the phases present at the end of crystallization. For any initial enantiomeric excess, the methodology yields distinct areas in the initial versus final temperature plane containing pairs of operating temperatures that are suitable for chiral resolution. Such operating map bears great potential in improving the design and optimization of chiral resolution processes by crystallization.

For drug substance manufacturing, it is necessary to have a robust crystallization process that can isolate quality active pharmaceutical ingredients with the desired crystal size distribution (CSD). This study presents a novel integrated crystallizer that combines cooling and antisolvent crystallization with wet milling and annealing operations to produce crystals with narrow size distributions. The incorporation of a wet mill and subsequent annealing vessel were carried out for size reduction and fines dissolution, respectively. The influential process parameters on CSD were identified by investigating the crystallization of verubecestat with the integrated system. Data-rich experimentation and enhanced process understanding were achieved by implementing process analytical technologies, such as attenuated total reflectance-Fourier transform infrared and focused beam reflectance measurement. Results show that the CSD can be tightly tuned through mill configuration, mill speed, and annealing temperature. Increasing mill rotational speed and using a denser rotor–stator teeth arrangement reduced crystal size, while a higher dissolution temperature was conducive to tightening CSD by dissolving fines and creating additional supersaturation for crystal growth. Results from the complete integrated system were compared to configurations without annealing vessel, which revealed that breakage, attrition, and secondary nucleation induced by milling led to wider CSD.