Crystallization of citicoline sodium by anti-solvent assisted with ultrasound

Abstract

Citicoline sodium tend to agglomerate during the crystallization process which can't be well solved by changing some conventional crystallization conditions. To solve this problem, an ultrasonic-assisted crystallization method was developed in this paper. The effects of ultrasound on the crystal metastable zone widths (MSZWs), induction time, crystal habit, and particle size distribution (PSD) were studied experimentally. The dynamic method was used to determine the solubility of Citicoline sodium in ethanol–water binary mixed solvents. The induction time and the MSZWs were measured under ultrasound and silent conditions. Moreover, the crystallization process was optimized using ultrasonic-assisted anti-solvent crystallization method. The influence of ultrasound on crystal habit during the crystallization process could be observed by optical microscope. Ultrasound optimized products can be characterized by scanning electron microscope (SEM), laser particle size analyzer, X-ray powder diffraction and infrared spectroscopy. The experimental results showed that the MSZWs and the induction time could be reduced by the application of ultrasonic irradiation. The agglomeration and crystal habit of Citicoline sodium could be improved by optimizing the crystallization process with ultrasound. After optimization, the mass yield was increased to 95 %, the median particle size DV (50) was about 10 μm and the PSD was narrower.