Metastable zone width, crystal nucleation and growth kinetics measurement in anti-solvent crystallization of β-artemether in the mixture of ethanol and water

The production of β-artemether, (3,12-epoxy-12 h-pyrano (4,3-j)-1,2-benzodioxepin, C16H26O5), an important active pharmaceutical ingredient for the treatment of malaria, uses crystallization as the purification step. This paper investigates the Metastable Zone Width (MSZW), nucleation and crystal growth kinetics of anti-solvent crystallization for β-artemether in ethanol + water system where water is the anti-solvent. Using a turbidity probe, the effect of process variables on MSZW was investigated, including initial the mass ratio of the solute to solvent, temperature, introduction rate as well as introduction location of the anti-solvent. The prediction model for MSZW was calibrated and proved reliable for this system. For anti-solvent crystallization of β-artemether in ethanol + water system, the chord length distribution data was collected using Focused Beam Reflectance Measurement, based on which the nucleation and crystal growth parameters were estimated using the method of moment. The crystal growth mechanism of β-artemether was also studied using a hot stage and imaging system and was found to follow a layer-by-layer growth mechanism.