Countercurrent Chromatography (CCC), a form of liquid-liquid chromatography, is an efficient preparative purification technique used for purifying active natural compounds, specifically those present in plants. The CCC technique relies on the use of a suitable solvent system that can be chosen from diverse solvent options. The solvents, spanning a large polarity range and selected from different solvent families, are used for compound separation. The solvent system selection procedure is laborious and time-consuming. Different strategies, which can help simplify the method of analytical method development, have been proposed over the past 30 years. Herein, the solvent system selection strategies for the conventional CCC and pH-zone-refining CCC techniques, based on partition coefficient measurement, theoretical modeling or mathematical calculation, have been comprehensively reviewed, focusing on the operation procedures. This review aims to address the difficulties faced during the CCC experiments and provide guidelines that can help develop a highly efficient and simple CCC solvent system.
