The authors are grateful to the Foundation for Science and Technology
(FCT, Portugal) for financial support through national funds
FCT/MCTES (PIDDAC) to CIMO (UIDB/00690/2020 and UIDP/00690/
2020) and SusTEC (LA/P/0007/2020). National funding by FCT,
Foundation for Science and Technology, through the individual research
grant (SFRH/BD/137966/2018) of Rami S. Arafah is also
acknowledged.
The separation of nadolol racemates under high pH reversed-phase using both the fixed-bed (FB) and the
simulated moving bed (SMB) preparative chromatographic techniques is reported after the previous published
work [1] where the Waters XBridge C18 adsorbent and an ethanol:water:diethylamine solvent mixture were
validated to allow the separation of the multicomponent feed mixture composed by four nadolol stereoisomers
into two pure racemates (two pairs of enantiomers).
In this work, the experimental preparative separations using one commercial fixed-bed preparative HPLC
Azura system equipped with one sole column of preparative dimensions (30 mm ID × 250 mm L) and one labscale
SMB apparatus (the FlexSMB-LSRE pilot unit) equipped with six semi-preparative columns (19 mm ID ×
100 mm L) are presented. Both systems use the Waters XBridge C18 adsorbent of 10 μm particle diameter. The
screening of the mobile phase composition elected the 30:70:0.1 (v/v/v) ethanol:water:diethylamine solvent
mixture to perform both FB and SMB preparative operations.
A large set of experimental, modelling and simulation results are presented, including pulses, measurement
and modelling of the adsorption equilibrium isotherms, and its validation through breakthroughs measurements.
The modelling and simulation steps allowed the prediction and the optimization of both the FB and SMB
operating conditions.
For FB, using a feed concentration of 9 g/L of an equimolar mixture of the two nadolol racemates, both were
recovered almost pure (at least 99.9 %), with a global system productivity of 3.06 gfeed/(Lbed.hr) and a solvent
consumption of 4.21 Lsolvent/gfeed. For SMB, the pilot unit’s pressure drops limits imposed a maximum internal
flow-rate of only 5 mL/min and, for a nadolol feed concentration of 2 g/L, both racemates were recovered 100 %
pure, with a system productivity of 0.13 gfeed/(Lbed.hr) and a solvent consumption of 6.19 Lsolvent/gfeed. Additional
simulation results showed that a SMB preparative unit can perform the 9 g/L nadolol racemate separation
with a system productivity of 3.61 gfeed/(Lbed.hr) and a solvent consumption of only 1.95 Lsolvent/gfeed using the
same average internal flow-rate as in FB operation. Even better SMB productivities can still be obtained using the
same feed or solvent flow-rates as in FB operation if the internal SMB flow-rates are allowed and not limited by
the system pressure drop.
The experimental results presented in this work validate the strategy of separating a four nadolol stereoisomers
mixture into two pure nadolol racemates, each one composed by a pair of nadolol enantiomers, using an
achiral C18 adsorbent through FB and SMB chromatographic techniques. Each nadolol racemate can later be
purified into pure nadolol stereoisomers using standard binary chiral FB and SMB chromatography. In this way,
this works introduces a real and experimental solution for the complete multicomponent preparative separation
of the four nadolol stereoisomers.
