IntroductionCentrifugal partition chromatography (CPC) is a liquid–liquid chromatography characterised by its solvent flexibility. The compounds undergoing separation are subjected to a continuous partition process between two immiscible phases in a column space free of solid support. In the context of green chemistry, it is important to substitute halogenated and petroleum‐based solvents commonly used in purification processes.ObjectivesThe main goal of the current study was to replace classical solvents used in CPC (e.g., hexane and methanol) by green and renewable alternatives.MethodsSolvents were first selected based on literature. Their commercial availability, price, recyclability, toxicity and ability to form two phases were particularly sought after.Key findingsThe new two‐phase solvent systems were evaluated for the purification of two compounds of interest: piperine and cannabidiol. Using these alternative two‐phase solvent systems allows us to isolate natural products with a high purity level (> 95%).ConclusionSubstituting petroleum‐based solvents with bio‐sourced, renewable alternatives reduces the environmental impact of CPC. Herein, new biphasic solvent systems were built using hexamethyldisiloxane, ethyl isobutyrate and 2‐methyl tetrahydrofuran in combination with ethanol and water. Furthermore, this research provides a scientific basis for developing new and sustainable solvent systems in CPC.