Preparative separation of nadolol racemates by fixed-bed and SMB liquid chromatography using C18 columns
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abstract
Nadolol is one representative beta-blocker pharmaceutical drug prescribed worldwide for relieve of
several diseases mainly related with the cardiovascular system. However, like other pharmaceutical
drugs, it is also related with some severe risks, such as depression, insomnia and cardiovascular failure,
among others. Some authors refer that this problem is related, or could be related, to the fact that
nadolol drug is still marketed as a mixture of equal amounts of its four stereoisomers.
In the pharmaceutical industry and in terms of preparative scale, there are two main strategies to obtain
pure enantiomer drugs. The first strategy is based on traditional methods of selective organic synthesis
that allows the attainment of large amounts of a single product but with the disadvantage of being large
time consuming. The other preparative strategy makes use of continuous separation processes based on
multicolumn and cyclic adsorptive liquid chromatographic techniques to achieve the resolution of a
racemic mixture. The use of such technologies allows, in a short period of time, the obtaining of enough
amounts of pure enantiomers needed to perform the main pharmacological studies in the first steps of
drug development.
Lately, our research group reported the pseudo-binary separation of RSR-nadolol stereoisomer, referred
in the literature as being the one responsible of the nadolol drug therapeutic action, by means of
simulated moving bed (SMB) chromatography using both coated Chiralpak AD and Chiralpak IA
immobilized chiral stationary phases (CSP).1,2 This technology is generally based on the use of chiral
adsorbents which must have enough recognition for all the chiral species.
In this work it is proposed an alternative strategy, implementing a first achiral separation step, to be
followed by two subsequent parallel chiral separation steps.3-5 In this first achiral step, C18 columns are
used to perform the separation of the two pairs of nadolol enantiomers (“racemate A” from “racemate
B”) under reversed-phase mode. The C18 achiral adsorbent allows the separation of the two pairs of
nadolol diastereomers, i.e., the first racemate (composed by the nadolol compounds 2 and 3) co-eluting
in the raffinate, and the second racemate (composed by the nadolol compounds 1 and 4) to be obtained
in the extract SMB stream. After this preliminary achiral separation step, two parallel SMB runs must be
carried out using a chiral stationary phase to achieve the complete separation of all the four nadolol
stereoisomers.
Extensive experimental and simulation results will be presented including solvent screening,
measurement of equilibrium adsorption isotherms, breakthrough measurements, and both fixed-bed
(Azura prep LC unit) and SMB (FlexSMB-LSRE unit) preparative separations using C18 columns.
This work was financially supported by: Project POCI-01-0145-FEDER-006984- Associate Laboratory LSRE-LCM funded by FEDER through COMPETE2020- Programa Operational Competitividade e lnternacionalização (POCI) -and by national funds through FCT- Fundação para a Ciência ea Tecnologia
