Crystallization behavior of an X-Ray Contrast Agent Intermediate at high Supersaturations and Temperatures
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This project comprises studies of crystallization of an aromatic amine, which is an intermediate in the production of the X-ray contrast agent Iohexol at GE Healthcare Lindesnes Site. Crystallizations from highly supersaturated solutions at high temperatures have led to discoveries that might contribute to improvements of the industrial crystallization process.The reaction crystallization was studied at constant temperatures in a lab scale batch reactor. Crystallization at 60, 75 and 90 ˚C was investigated, and high initial supersaturations made it possible to study a phase transformation phenomenon with FBRM and PVM in situ. A broad study was carried out with water as solvent, and the supersaturation lower bound of the phase transformation phenomenon was determined at each temperature. Based on observations from FBRM, PVM and SEM, the phenomenon is characterized as a nucleation of relatively few particles followed by a rapid growth and a phase transformation. The chord length distribution before phase transformation highlights a large population of particles above 150 μm. During the transformation, a secondary nucleation takes place, with the formation of a more stable solid phase with a chord length distribution without counts above 150 μm. The solid phases are studied by XRD, and an increase in crystallinity during the period of phase transformation is observed. The concentration of the aromatic amine is measured to be stable in the period of transformation, approximately two times the expected solubility. Experiments at supersaturations below the phenomenon lower bound resulted in formation of spherical particles, and no phase transformation was observed in 10 hours. The reaction crystallization of the aromatic amine was also performed from a process solution sampled from the industrial process at GE Healthcare. The solvent compostion of water and methanol and high concentrations of salts in this solution were shown to have a considerable effect on the crystallization, observed both through morphology observations and comparison of FBRM data. A phase transformation was also observed in crystallization from the process solution. The metastable solid phase was stable for several minutes, in contrast to similar crystallizations performed with water as solvent. XRD showed that the large particles of a so far undiscovered solid phase are going through a phase transformation to a crystalline solid known from former studies. Polymorphism was suggested as the most reasonable explanation for the difference in XRD spectra and the observed transformation. A qualitative evaluation of the phenomenon in an industrial perspective highlights the potential of the large particles in a flow-reactor regime, regarding reduced process time and beneficial filtration properties.