Process Design for Antisolvent Crystallization of Erythromycin Ethylsuccinate in Oiling-out System

Abstract

The crystallization process of erythromycin ethylsuccinate in a tetrahydrofuranwater system was investigated. Results show that oiling out occurs under several conditions; hence, a phase diagram with a liquid-liquid equilibrium area was established experimentally. For improved understanding of oiling-out crystallization, a series of in-situ tools, including FBRM, ATR-FTIR, and PVM, were applied to monitor the oiling-out phenomenon and the subsequent nucleation of erythromycin ethylsuccinate. SEM images were employed to analyze the influence of oiling out on the properties of the final crystals. The nucleation mechanism of erythromycin ethylsuccinate differs significantly depending on the location of the line of operation.The combination of cooling method and anti-solvent crystallization can be achieved with fundamental data of the phase diagram to suppress the oiling out phenomenon and obtain crystal products with high quality. The ternary phase diagram is of great importance in the process design of anti-solvent crystallization for an oiling-out system.

Oiling‐Out Crystallization of Beta‐Alanine on Solid Surfaces Controlled by Solvent Exchange

“…[ 1,2 ] An antisolvent crystallization is a method in crystallization from a liquid mixture, where the crystal nucleation and growth is driven by solubility reduction with change in the solvent composition. [ 3–5 ] Antisolvent crystallization is usually at low cost and with high efficiency. In a range of crystallization systems, oiling‐out or liquid–liquid (L–L) phase separation frequently occurs, which is the appearance of droplets in supersaturated solution.…”

pH-dependent oiling-out during the polymorph transformation of disodium guanosine 5′-monophosphate

“…Oiling-out is an extremely common phenomenon in industrial crystallization and can be observed in most processes of macromolecular crystallization, such as that of proteins 1,2 and polymers. 3,4 This phenomenon has become more evident since comprehensive studies on unbuffed lysozyme-salt solution have been reported. 5,6 The oiling-out phenomenon particularly occurs during cooling and anti-solvent crystallization.…”

“…Many researchers have studied the LLPS behavior using phase diagrams and thermodynamics. According to Li et al 8 the ternary phase diagram is critical in the process design of anti-solvent crystallization for an erythromycin ethylsuccinate oiling-out system. Yang et al 9 drew a ternary phase diagram of butyl paraben, water, and ethanol and combined it with process analytical technology (PAT) to increase the understanding of complex crystallization processes.…”

Oiling-out Crystallization of Beta-Alanine onSolid Surfaces Controlled by Solvent Exchange

“…Crystallization is one of the most important separation and purification techniques used in the pharmaceuticals and chemical engineering to produce a wide range of pure materials 1,2 . A method in crystallization from a liquid mixture is antisolvent crystallization, where the crystal nucleation and growth is driven by solubility reduction with change in the solvent composition [3][4][5] . Antisolvent crystallization is usually at low cost and with high efficiency.…”