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Research Project
Multicomponent chiral separation by preparative and simulated moving bed chromatography
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Fixed-bed and simulated moving bed chromatography using achiral and chiral adsorbents for the complete preparative separation of a quaternary mixture
Publication . Arafah, Rami; Ribeiro, António E.; Rodrigues, Alírio; Pais, Luís S.
Nadolol is a nonselective beta-adrenergic receptor antagonist (beta-blocker) pharmaceutical drug, widely used in the treatment of cardiovascular diseases, such as hypertension, ischemic heart disease (angina pectoris), congestive heart failure and certain arrhythmias. This drug is still being marketed as a mixture of four stereoisomers in spite of the clear evidences that only one of its four stereoisomers has the desired therapeutic effect.
Preparative liquid chromatography is actually an accepted route in industry to obtain enantiomeric pure drugs. Today, the combining of different chromatographic technologies, such as fixed-bed and simulated moving bed together with the use of achiral and/or chiral adsorbents are an important improvement in performance of preparative separation of multicomponent chiral drugs into its single pure stereoisomers. This work confirms this improvement using the referred strategy with mobile phase composition optimization at both normal and reversed-phase mode. Different separation strategies were designed and optimized, enlarging the packing materials possibilities, from fully chiral (Chiralpak) to achiral (C18) combined with chiral separation. For each separation step, the optimization of the solvent composition was carried out with pure alcohol, alcohol-hydrocarbon and alcohol-water mixtures, all with a basic modifier (diethylamine), taking into account the strong basic nature of the nadolol.
Separation of nadolol racemates by high pH reversed-phase fixed-bed and simulated moving bed chromatography
Publication . Arafah, Rami; Ribeiro, António E.; Rodrigues, Alírio; Pais, Luís S.
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.
Fixed-bed and simulated moving bed chromatography using achiral and chiral adsorbents for the complete preparative separation of a quaternary mixture
Publication . Arafah, Rami; Ribeiro, António E.; Rodrigues, Alírio; Pais, Luís S.
Nadolol is a nonselective beta-adrenergic receptor antagonist (beta-blocker) pharmaceutical drug, widely used in the treatment of cardiovascular diseases, such as hypertension, ischemic heart disease (angina pectoris), congestive heart failure and certain arrhythmias. This drug is still being marketed as a mixture of four stereoisomers in spite of the clear evidences that only one of its four stereoisomers has the desired therapeutic effect.
Preparative liquid chromatography is actually an accepted route in industry to obtain enantiomeric pure drugs. Today, the combining of different chromatographic technologies, such as fixed-bed and simulated moving bed together with the use of achiral and/or chiral adsorbents are an important improvement in performance of preparative separation of multicomponent chiral drugs into its single pure stereoisomers. This work confirms this improvement using the referred strategy with mobile phase composition optimization at both normal and reversed-phase mode. Different separation strategies were designed and optimized, enlarging the packing materials possibilities, from fully chiral (Chiralpak) to achiral (C18) combined with chiral separation. For each separation step, the optimization of the solvent composition was carried out with pure alcohol, alcohol-hydrocarbon and alcohol-water mixtures, all with a basic modifier (diethylamine), taking into account the strong basic nature of the nadolol.
Complete separation of the quaternary mixture of nadolol stereoisomers using preparative and simulated moving bed chromatography
Publication . Arafah, Rami; Ribeiro, António E.; Rodrigues, Alírio; Pais, Luís S.
The separation and purification of high added value products by liquid chromatography is a very
popular technique. The development of more stable and efficient stationary phases, together
with the design of innovative and more flexible separation processes, enhanced the use of
chromatographic processes, particularly at preparative and industrial scales through fixedbed
and simulated moving bed (SMB) technologies. Fixed-bed and SMB techniques are more and
more used in the separation of a wide range of products for the pharmaceutical, fine chemistry,
biotechnology and food industries. In this context, one of the actual main challenges concerns
the design and optimization of these chromatographic processes for challenging
multicomponent separations. This includes the development of new and innovative
chromatographic processes, combining different design strategies and modes of operation, with
different types of stationary and mobile phases.
Complete separation of the quaternary mixture of nadolol stereoisomers using preparative and simulated moving bed chromatography
Publication . Arafah, Rami; Ribeiro, António E.; Rodrigues, Alírio; Pais, Luís S.
The separation and purification of high added value products by liquid chromatography is a very
popular technique. The development of more stable and efficient stationary phases, together
with the design of innovative and more flexible separation processes, enhanced the use of
chromatographic processes, particularly at preparative and industrial scales through fixedbed
and simulated moving bed (SMB) technologies. Fixed-bed and SMB techniques are more and
more used in the separation of a wide range of products for the pharmaceutical, fine chemistry,
biotechnology and food industries. In this context, one of the actual main challenges concerns
the design and optimization of these chromatographic processes for challenging
multicomponent separations. This includes the development of new and innovative
chromatographic processes, combining different design strategies and modes of operation, with
different types of stationary and mobile phases.
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Funders
Funding agency
Fundação para a Ciência e a Tecnologia
Funding programme
POR_NORTE
Funding Award Number
SFRH/BD/137966/2018