Investigation Of Anti-sovlent Crystallization Of β-Artemether

β-artemether is an important macrocyclic lactone active pharmaceutical ingredient, and recommended by WHO for treating of malaria. Crystallization is the crucial process for separation and purification ofβ-artemether. Purity, crystal shape, polymorphism, and crystal size distribution (CSD) are crucial product quality factors, and these factors greatly impact both downstream processing and bioavailability ofβ-artemether product. In this study, after considerable investigation, thermodynamics and kinetics experiments were conducted for systematic studies ofβ-artemether crystallization using process analytical technology.In this work, the solubilities ofβ-artemether in seven organic solvents, ethanol + water, and methanol + water solvent mixtures were measured using the gravimetric method, and the experimental solubility data were correlated with empirical equation and idea solution model, models for prediction of solubility were developed.Polymorphism ofβ-artemether was investigated, and two crystal structures ofβ-artemether were confirmed using X-ray powder diffraction technique, X-ray single crystal diffraction technique, and molecular kinetics simulation method. One is monoclinic crystal with spacegroup of P21, the other is triclinic crystal with spacegroup of P-1. The crystal habit ofβ-artemether was predicted based on AE model BFDH model.Supersaturation is the driving force of crystallization, which determines nucleation and crystal growth. The method for on line measurement of solution concentration was developed successfully. In this method, UV-Vis fiber spectroscopy coupled with a circulated system was designed for acquiring of raw UV-Vis spectra, and the model for prediction of solute concentration was developed based on OSC corrected UV-Vis spectra.The metastable zone width (MSZW) was measured by on line turbidimeter, and the calibrated model for prediction of MSZW was developed. The nucleation and crystal growth were investigated using Focused Beam Reflectance Measurement (FBRM), the experimental kinetics data were analyzed and calibrated by moment method, and the parameters for kinetics equation were obtained based on experimental kinetics data.The crystal growth mechanism was confirmed according to the findings observed using the hot stage camera system.Research results of this study would provide the fundamental data for the manufacturing ofβ-artemther.