Centrifugal
partition chromatography (CPC) is an emerging separation
technology in pharmaceutical and natural product purifications, reaching
recently industrial-scale solutions. Because both the stationary and
mobile phases are liquids in CPC, the solvent consumption of such
separation processes is considered significant. Thus, automation is
highly required in the preparation and recycling of the solvent mixtures
for economical (i.e., continuous) CPC operation. Here, we report a
feasible solution for this industrial issue, including the concept,
algorithm, and instrumentation of solvent system handling. For majority
of ternary solvent systems used in CPC separations, the linear correlation
between the density and composition of the phases was recognized and
utilized during the continuous solvent recycling. Hence, an efficient
density-based composition adjustment algorithm was established in
a mixer-settler unit using Coriolis flow meters for precise density
monitoring of the upper and lower phases of the biphasic liquid system
(BLS). In addition, a complete cascade consisting of a buffer, waste,
a recycler (evaporator), and mixer-settler units was designed around
the industrial-scale CPC device. The proof of concept was demonstrated
by sequential industrial-scale CPC separations of a binary model mixture
in the n-hexane/methanol/water (5/4/1, v/v/v) solvent
system, followed by the purification of a crude steroid active pharmaceutical
ingredient performed in the methyl isobutyl ketone/acetone/water
(2/2/1, v/v/v) solvent system. The reproducibility of chromatographic
performance and the productivity of the mixer-settler and evaporator
units were satisfactory, enabling a robust and continuous operation
of the developed separation process.