Operating mode and parameter selection in liquid–liquid chromatography

The presence of a liquid stationary phase in liquid–liquid chromatography (LLC) allows for high versatility of operation as well as adaptability to different sample types and separation tasks. LLC, also known as countercurrent chromatography (CCC) or centrifugal partition chromatography (CPC), offers the user a variety of operating modes, many of which have no direct equivalent in conventional preparative liquid–solid chromatography. These operating modes have the potential to greatly improve LLC separation performance compared to the standard “classical” isocratic batch injection mode, and they often require minimal to no addition of equipment to the standard set-up. However, reports of the use of alternative LLC operating modes make up only a fraction of the literature. This is likely due, at least in part, to the lack of clear guidelines and methods for operating mode and parameter selection, leaving alternative process options to be avoided and underutilized. This review seeks to remedy this by providing a thorough overview of the available LLC operating modes, identifying the key characteristics, advantages and disadvantages, and areas of application of each. Additionally, the equations and short-cut models aiding in operating mode and parameter selection are presented and critiqued, and their notation is unified for clarity. By rendering LLC and its alternative operating modes more accessible to current and prospective users, it is hoped to help expand the application of this technology and support the achievement of its full potential.