A two-column version of a multicolumn, semi-continuous, open-loop chromatograph for chiral separation is presented and validated experimentally. The heart of the process is a flexible node design and cyclic flow-rate modulation that succeed at keeping the mass-transfer zone inside the system without resorting to any recycling technique. One advantage of this streamlined design is the simplicity of its physical realization: regardless of the number of columns, it only requires two pumps to supply feed and desorbent into the system, while the flow rates of liquid withdrawn from the system are controlled by material balance using simple two-way valves. A rigorous model-based optimization approach is employed in the optimal cycle design to generate a solution that is physically realizable in the experimental apparatus. The optimized scheme for two-column operation supplies fresh feed into the system where the composition of the circulating fluid is closest to that of the feedstock fluid, and recovers the purified products, extract and raffinate, alternately at the downstream end of the unit while desorbent is supplied into the upstream end of the system. The feasibility and effectiveness of the two-column process are verified experimentally on the separation of reboxetine racemate, a norepinephrine re-uptake inhibitor, under overloaded conditions. Our set-up employs an automated on-line enantiomeric analysis system, comprising an analytical HPLC set-up with two UV detectors to monitor the composition profile at the downstream end of one of the columns; this monitoring system does not use a polarimeter. (C) 2010 Elsevier B.V. All rights reserved.