Antisolvent Crystallization of Erythromycin Ethylsuccinate in the Presence of Liquid–Liquid Phase Separation

Abstract

The nucleation point of erythromycin ethylsuccinate crystallization with liquid–liquid phase separation, also called oiling-out, was determined through nucleation analysis. To achieve successful monitoring of nucleation events, focused beam reflectance measurements were performed during antisolvent crystallization. The induction time of the oiling-out system was determined and correlated with classical nucleation theory. The induction time increases with decreasing solubility under a constant thermodynamic driving force. The position of a nucleation point may be determined by comparing the nucleation energy barrier and supersaturation generated in solute-rich and solute-lean phases. The estimated interfacial energy is in the range of 0.422–1.315 m·J/m2, which is in agreement with nucleation theory. A homogeneous nucleation process was observed under high supersaturation, and heterogeneous nucleation took place at low supersaturation. The growth mechanism was identified with the interfacial tension. The continuous growth dominates the whole growth process.

A spatiotemporal route to understanding metal halide perovskite crystallization

“…The organic ammonium cations preferentially segregate to the ASdeficient phase, hindering crystallization. This effect has been reported previously in both the halide perovskite 49 and in organic pharmaceutical literature l. 50 In our work, initial nucleation was observed to occur before liquid-liquid separation in three reactions (dmed in GBL:DMF, aep in GBL:DMF and dedap in GBL), owing to the presence of weak GBL-reactant interactions. Images are shown in Figure S3b.…”

Industrial Crystallization in China

“…The crystal morphology mainly involves the crystal habit and CSD and has significant impacts on the filtration performance, dissolution rate, bulk density, hygroscopicity, and preparation of the pharmaceutical crystals. To modify the crystal habit, effect factors have been investigated including solvent system, seed, supersaturation, e.g., cooling profile, adding rate of the antisolvent, mixing, e.g., agitation, impeller type, string rate, and additives [17][18][19][20][21]. Li et al [19] evaluated the effect of supersaturation on the crystal shape and discovered that the different supersaturation levels led to varying aspect ratios of the final product.…”

“…To modify the crystal habit, effect factors have been investigated including solvent system, seed, supersaturation, e.g., cooling profile, adding rate of the antisolvent, mixing, e.g., agitation, impeller type, string rate, and additives [17][18][19][20][21]. Li et al [19] evaluated the effect of supersaturation on the crystal shape and discovered that the different supersaturation levels led to varying aspect ratios of the final product. Spherical crystallization, which has been extensively developed in the pharmaceutical field, was performed and studied by Zhang et al [20] and Yang et al [21] to enhance the flowability and control the size distribution of particles.…”

“…When the solubility of a solute is known, it is much simpler to choose a crystallization method, select appropriate solvents, and calculate the yield. For more complex systems, the phase diagrams should be determined to instruct the most rational region for crystallization operation [19,28]. Thermodynamics also has a considerable influence on solid forms.…”

A Pathway to First Crystals for Substances Prone to Liquid‐Liquid Phase Separation

“…Additionally, the occurrence of LLPS was also attributed to (i) large differences in polarities of solvents utilized to solubilize the drug 29, (ii) low aqueous solubility, which is also due to increased lipophilicity 30, 31, (iii) rapid generation of highly supersaturated solutions 32, and (iv) increased supersaturation via the use of an amorphous solid to enhance aqueous solubility 7.…”